Spionage, Kriminalität und Politik prallen in Mexiko-Stadt aufeinander. Ein brillanter, aber selbstzerstörerischer CIA-Agent, sein junger und ehrgeiziger mexikanisch-amerikanischer Schützling und der vorbildliche, aber geheimnisvolle Bürgermeister kämpfen um die Macht, während das mörderischste Drogenkartell der Welt die Stadt belagert.

Wayne works with the joint Mexican-American "Fusion Center” to track the sicarios responsible for the recent bloodshed. Isa ignores orders to stay in the embassy and instead pursues a lead to the Guerrero Cartel. And Lalo puts his career at risk, battling the Mexican President for control of the narco investigations.

Isa recruits her first "asset," a source with connections to the cartel, but stretches ethical boundaries in the process. A visitor from Wayne's past dredges up unpleasant and violent memories. Lalo risks his relationship with his wife to pursue a rape prosecution against children of the rich and powerful. And Bautista’s plan for the city starts to become clearer.

Wayne, Isa and Pamela undertake a dangerous mission, infiltrating a corrupt banker who could lead them to the Guerrero cartel. Lalo and Isa start to bond while working on an art exhibition, but their past conflicts re-emerge to threaten their friendship. And Bautista’s sicarios conduct a mysterious operation that ends up having terrifying consequences for the city.

Wayne, Isa and Romero work frantically to rescue the hostages. Lalo and his police force do the same, but Lalo has his own agenda. Bautista carries out a mysterious plan involving his sicarios. And Wayne and Isa eventually come a terrible realization about why Bautista invaded the city.

Lalo's left reeling from the events of the last episode. He takes Isa on a trip to his family’s estate outside of the city, which allows Isa to learn one of Lalo’s biggest secrets. Meanwhile, Wayne discovers Bautista’s weakness and uses it to lay a trap for the narco. But Bautista is also laying a trap of his own.

Isa breaks with Wayne over the recent bloodshed and engages in risky behavior, both professional and personally. Wayne visits a figure from his past, and in flashback, we learn the tragic origins of his hatred for Bautista. Bautista takes a physical and spiritual journey into the hills of Guerrero, coming to a decision that will have horrible consequences for Lalo and the entire country of Mexico.

Wayne's off-the-books operations finally catch up to him as Isa's fiancé pursues a lead that could put both Wayne and Isa in jail. Isa has to create a fake asset to cover up for Wayne’s misbehavior. Meanwhile, Bautista threatens Wayne’s life, but mysteriously, and ominously, lets him live. Veronica starts to realize the truth about her marriage. And Lalo gets his hands dirtier than ever before.

Lalo has a head-to-head confrontation with the Guerrero cartel, with fatal results. A risky Hail Mary from Wayne puts him and Isa into bloody conflict with the Northern Federation. And Isa and Lalo come to a realization about their relationship.

In the aftermath of the previous episode, Wayne, Isa, Veronica and Lalo all come to realizations about their lives and relationships. By the season’s end, the previous alliances have been destroyed and new ones are being built. And our main characters have to prepare for war, with new battle lines drawn.