The game puts four human playable or AI-controlled Survivors of an apocalyptic pandemic against hordes of the Infected. Regular Infected are controlled by the game AI, while human players can control up to four mutated Special Infected with special abilities in Versus mode. The goal of Left 4 Dead for the Survivors is to help each other make it through a level to safety. Infected players must cooperate to stop them.

No Mercy, focused on moving towards a Hospital for evacuation. Takes place in an apartment building, subway station, sewer, Mercy Hospital, and a Rooftop Finale. The rescue vehicle that saves the Survivors is a News 5 Helicopter.

Crash Course takes place directly after the No Mercy Rescue. The News 5 Helicopter crashes in an area close to The Turnpike in Death Toll. The helicopter is caused to crash after Zoey kills the pilot who is, in fact, infected. This campaign is focused on delivering a full multi-player campaign in just 1/2 hour. It was released for download on the 29th of September 2009.

Death Toll takes place from an abandoned highway, the drainage system of Riverside, a church, the town of Riverside and the Boathouse Finale. In which the Survivors contact two civilians; John and Amanda Slater. A boat arrives to rescue the Survivors.

Dead Air, a campaign focused on getting through an Infected greenhouse, through a metropolitan area, an air station terminal, and finally, a last stand at a Runway Finale. Dead Air's rescue vehicle is a C-130 Hercules that has run out of fuel, and the Survivors must wait for it to fuel before they are rescued.

Blood Harvest, a campaign that revolves around getting to a military base in a rural area. This campaign begins with a wooded area, continues on to a train yard, and culminates in a Farmhouse Finale reminiscent of the film Night of the Living Dead. An M93 Fox Armored Personnel Carrier is the rescue vehicle in Blood Harvest's campaign.

The Last Stand, this campaign has only one level, The Lighthouse. This campaign can only be played after downloading the Survival DLC. It is located in the woods, with a large lake off to the side, unreachable by the Survivors. As it can only be played in Survival Mode, there is no rescue vehicle that arrives to rescue the Survivors and always ends with the Survivors' death.

According to Valve, the Infection has spread to the southern United States, where the sequel picks up 1 week after the events of the first game (3 weeks after the first infection).Left 4 Dead 2 will feature three new Infected (the Charger, revealed in the E3 '09 trailer; the Spitter, revealed on July 20th, 2009 and the Jockey), 20 new weapons including melee weapons, new items, upgraded Infected (limbs can be taken off), the Uncommon Common Infected (such as the hazmat-suited Infected that are immune to fire), five new campaigns which are said to connect unlike the original's, new Survivors, and one new game mode, entitled 'Scavenge Mode'.

This is the first campaign of the game, taking place in Savannah, GA. The Survivors find themselves caught up in the chaos of a recent outbreak of the Infection, and have to fight their way through the still partially functional city to to a shopping mall, where they make their escape in a muscle car

Upon finding the freeway out of Savannah blocked by abandoned cars, the Survivors are forced to leave their vehicle and make their way on foot to the Whispering Oaks amusement park, where a nearby train station will provide them with an escape route out of Georgia to a rumored safe zone near New Orleans, LA.

The train in which the Survivors escaped Savannah has derailed and crashed outside a small town in rural Louisiana. Now they have to fight their way through the nearby swamps and an abandoned shantytown to a giant plantation house, where they have to fight the horde until a rescue boat comes to save them.

Almost nothing is known about this campaign - the Survivors' plan to escape from the infected zone have failed one more time, and they are forced to fight their way through a partially flooded industrial complex and find an alternate way to reach New Orleans.

As the morning sun begins to rise, the Survivors finally manage to reach New Orleans, only to find the city completely overrun by the Infected. They have to make their way through the streets of the French Quarter, a cemetery and the military's abandoned quarantine zone until they finally arrive at a partially collapsed table bridge. On the other side is a military helicopter waiting to take the Survivors out of the city to a flotilla of commandeered cruise ships in the Gulf of Mexico, where the last remnants of humanity in the area have regrouped, safe in the knowledge that the Infected can't swim...so far...