Missing is the longest questline in the entire game, and is the most fleshed out and detailed. It is thinly strung across many, many other quests in the game. It is arguably the game's main quest.
This quest is spread thinly spread over most, if not all, quests in the game. Ergo, every character, except for Vince's Gang, plays a part in it at some point or another, as they all tie in to this quest.
The Survivalists have headed over to Fort Kohai, and they meet Ida Marchbanks, a grieving woman who's husband Lou Marchbanks was kidnapped over a month prior. Ida doesn't want to ask any old person to look for Lou, so the Survivalists perform several tasks for Fort Kohai, the most important to these quests being: Fat Neils vs McCoys, Devil's Gulley and The Road to Santa Maddalena. After completing some and gaining the respect of Ida, she will be willing to give the quest to the Survivalists.
She explains that Lou went missing in the Buckeye area, so they must look there. The Survivalists navigate to the area, and, after scanning the environment, they find food wrappings and rocket launcher ammunition in a workshop. The Survivalists bring them back, and Wyatt Ingalls calls a meeting to discuss the recent happenings. The Fort deduces that the grenade MUST be from a well-equipped and seemingly evil community up north: Los Ceros.
So, the Survivalists head into Red Strain territory to find the group. They do so, and feel that they have to gain access to Felipe Espinosa's personal compound. So, the Survivalists quickly hear of a leadership dispute between two siblings. Elfego Arcine and Em Arcine. The group does many quests for these two, as being a member of the inner circle is seen as a way into the compound. The final quest for these two is for you to kill Cornelius Chacon, a former associate of Espinosa. The reward, according to Felipe's lieutenant Mike Doolin, is a place in the Inner Circle. The player decides which one to work for, and completes the task.
Either Em or Elfego are promoted to the Inner Circle, and the Survivalists ask for a favour: check the cells for a man. After much persuasion, Em/Elfego does so, and they are horrified to find Lou Marchbanks in the cell. The Survivalists return to Fort Kohai and feed this information back. Wyatt Ingalls wants to peacefully negotiate with Los Ceros. Bud Anderson, on the other hand, wants to kill all of Los Ceros to get to Lou. Depending on the players actions, one will win.
If Bud wins, the group attempts to negotiate with Mike Doolin, but thing's get heated during negotiations and Fort Kohai's best soldier Chris Kane is shot dead in the process.
If Wyatt wins, the aforementioned negotiations occur, however Wyatt is killed as opposed to Kane, by Ida Marchbanks, who wanted a war so that Lou could be broken out of Felipe's compound. In both, the Arcine that the Survivalists got elected is killed in cold blood by Doolin for treachery.
Either way, all out war breaks out in the Sonaran Desert, and Santa Maddalena may be obliterated depending on the actions of the Survivalists. The Survivalists either siege Los Ceros or infiltrate the compound from the exterior fence. They find Lou after confronting Espinosa, and he may be taken back to Fort Kohai. However, it is discovered that Lou is a Living Infected, a trait shared with the now deceased Charlie Cashman. He is put down, and the Survivalists return to Felipe for answers.
Espinosa explains that he has heard odd sounds coming from somewhere in the southeast of the desert. He implores that the group investigates. Felipe can now be killed, or recruited to the Survivalists. Either way the group investigates this, and finds a sprawling army base containing the remnants of F.E.M.A., a military group lead by chief of research Clara Allison.
After forcing F.E.M.A. into surrender, Clara explains that their group is in the desert researching a cure, kidnapping survivors as 'test subjects.' These became the Living Infected. It's revealed that Joe Wheeler caused the apocalypse as trials into erectile dysfunction medication resulted in abnormalities in volunteers, leading to the epidemic. It's also revealed that Patient Zero, a pivotal part of F.E.M.A.'s research, escaped a while ago, and it's found to be Alice Ivers. She promptly runs away, leaving Joe distraught.
Joe will eventually leave the desert (possibly with Isham) to get to Vancouver and track Alice down. The game then ends, and the quest is complete.