Causes

An engine needs three basic ingredients to run: fuel, air flow, and ignition (spark). Disruptions to any of these can cause misfire. Fuel and air amounts are controlled very precisely, and the engine is sensitive to very small changes.

Some common causes are:

• Fuel
  • Insufficient fuel pressure
    • Fuel pump is worn out, or not getting power (wiring)
    • Fuel filter is clogged.
    • Broken or leaky fuel line
  • Malfunctioning fuel injectors
    • Clogged or worn out
    • Not receiving power or signal (wiring)
  • Sensors (ECT, O2 etc.)
    • Bad sensor
    • Bad connection
• Air
  • Air filter - Clogged or incorrectly seated
  • Dirty throttle body or idle valve
  • Dirty intake or exhaust valves
  • Clogged or collapsed catalytic converter
  • Leaks in the air intake, hoses (vacuum, PCV or EGR), or filter housing
  • Sensors (TP, MAF, MAP, IAT etc.)
    • Dirty or worn out
    • Electrical connection (wiring)
• Ignition
  • Spark plugs
    • cracked, dirty, worn out, bad gap
    • weak or no power
  • Spark plug wires (older vehicles without coil-on-plug)
    • Loose, cracked or worn out wires
  • Coils
    • cracked or worn out
    • no power or signal (wiring)
  • Timing
    • Sensors (CMP, CKP, KS etc.)
      • bad sensor
      • bad connection
    • Bad PCM computer (rare)
    • Distributor (older vehicles without electronic ignition)
      • dirty, cracked or worn out cap
      • moisture ingress
      • worn out or misaligned rotor
    • Faulty ignition control module or connection (only some vehicles)

ELECTRICAL NOTE:

A weak alternator or battery can cause any of previously mentioned components to not work properly.

Also, make sure all fuses and relays are good, and the battery terminals are tight and clean.

General engine wear can also cause poor/incomplete combustion

• Poor cylinder compression - Engine wear or damage causes cylinders to seal poorly. As a result, the fuel and air mixture is not sufficiently compressed to support good combustion.
  • Worn out or failed piston rings
  • Worn out or scored cylinder walls
  • Dirty or worn out valves and seats
  • Loose spark plugs
• Worn valvetrain
  • Camshaft
  • Various valve linkages (pushrods, rollers, springs, rockers etc.)
  • Timing chain, belt, or sprockets
  • Valve adjustment (some Japanese cars)
  • V-Tech, VVT etc.
    Many modern cars have systems to modify or the valve timing or cam phasing. Various systems are used such as hydraulics, electronics or combinations of both. These can sometimes wear out , or fail from things like sludgy oil or burned out solenoids.
  • Cylinder deactivation (AFM, DOD, etc.)
    Many new cars employ cylinder deactivation to save fuel. Presently, they are problematic and unreliable. Often it is beneficial to disable them completely.

Symptoms

  Besides the warning light, you may experience other symptoms.  A misfiring engine is not running efficiently, will lack power, and will often run or idle poorly overall. Depending on the severity, the engine may hesitate or stumble when trying to accelerate. You will feel interruptions in the normal vibrations of the engine, and hear the sound becomes rough as well. Some people compare the sound to making popcorn. Misfires can happen when idling, and while driving.

If you connect to your vehicle's computer with a diagnostic scanner, it may report (one or more of) these trouble codes:

P0300 - Random/Multiple Cylinder Misfire Detected
P0301 - Cylinder 1 Misfire Detected
P0302 - Cylinder 2 Misfire Detected
P0303 - Cylinder 3 Misfire Detected
P0304 etc.

Peripheral symptoms

  Sometimes, misfiries can also be associated with other symptoms. Fixing the misfire could make other problems go away. And fixing other problems can make the misfires go away. You may see other diagnostic codes along with the misfire ones. For example, and incorrect fuel mixture can cause misfiring, and trip oxygen sensor faults at the same time.

Example of mild engine misfire:

Diagnosing

Here are the easiest tests you can do to verify some of the possible causes

• Spark test
  
  Pull out one spark plug at a time. A spark plug tip that is black with carbon, or wet with fuel, it is indicative of misfiring. Disconnect EFI fuse, lay the spark plug on the engine block so it's grounded (or use inexpensive ground clip) and briefly crank the engine. Make sure the plug produces a good hot spark.
• Fuel test
  
  Attach a pressure gauge to the fuel port, turn the key on for a few seconds and then off. Repeat a few times and then wait. Fuel pressure should build up (research your spec), level off, and hold there within a few PSI for about 20 minutes. Lack of pressure usually indicates a problem with the pump/filter assembly.
• Compression test
  Disconnect fuel. Remove spark plugs one at a time, and insert pressure gauge. Disconnect EFI fuse. Crank the engine. Each cylinder should generate at least 100 PSI. Any cylinder-to-cylinder differences of more than 10% should be investigated further. Research the "wet/dry" and "leakdown" test.
• Isolate components
  If you have some cylinders that aren't misfiring, then try putting components from those good cylinders into the misfiring ones (spark plugs, coils, injectors etc.)
• Catalytic converter
  
  Gently bump your catalytic converters. If they rattle or you suspect they are plugged up, remove the upstream oxygen sensor and see if the engine runs better. Or plug in a gauge to measure back-pressure. This should be done in tandem with diagnostic tools to make sure O2 sensor are producing the expected readings.
• Vacuum leak
  Spray starting fluid around the air filter housing, intake manifold and the various hoses. If the engine speeds up or gets louder then you have a vacuum leak. Or mist some water and look for decreasing RPM. Sometimes you can hear the air hiss from the leak point. Vacuum routing can extend all the way to brake boosters and your fuel tank EVAP system and there are hoses and check-valves along the way that can fail.
• Engine Banks
  Some engines, such as the 'V' shaped engine (V6, V8 etc.) have cylinders divided into banks. The image below shows a V8 engine. If you are getting misfires on only one bank, for example cylinders 1,3,5 or 7 , then that usually indicates an intake or head gasket failure in one bank. Cylinder numbering usually starts at the front of the engine on the driver's side.

   

Hey great work Joe

Testing fuel injectors

How to test fuel injectors using a "noid" light

Videos

Troubleshooting your ignition system

Wait until dark. Start the engine and pop the hood. Examine spark plug wires from the coil to the spark plug. See if it's arcing on any metal parts. (it's easy to see at night)

You can use a spray bottle of water and spray the length of the wire. See if that causes arcing to metal. If it does, install a COMPLETE set of new spark plug wires.

You can also try an HEI spark tester.

They're inexpensive. (around $10). How to use a spark tester.

(thanks @jack62)

What is a misfire?

  An engine makes power by combusting a fuel and air mixture inside a cylinder, which pushes the pistons, driving the vehicle forward. These combustion events happen hundreds of times every second. When combustion fails to occur, it is called a misfire.  Most of the components of the engine exist to maintain this combustion, which why there are so many different possible causes for a misfire to happen.

When misfires happen repeatedly, the computer will illuminate a trouble light on your instrument panel. If you keep driving a car that is misfiring, then it will cause damage to other components over time, such as your catalytic converter (thousands of dollars to replace).  If the engine is misfiring badly enough, the engine warning light on your instrument panel will flash, indicating that you should stop the vehicle right away, because driving further can cause immediate damage.