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Following an early career in Mexican telenovelas, Luna had his breakthrough in the critically acclaimed 2001 film Y tu mamá también. During the 2000s, he appeared in both Mexican and American films, including Frida, Open Range, Dirty Dancing: Havana Nights, The Terminal, Criminal, Milk, Sólo quiero caminar, and Rudo y Cursi. In the 2010s, his films included the science fiction film Elysium, the comedy Casa de mi Padre, and the animated musical The Book of Life. From 2018 to 2020, he starred as the drug trafficker Miguel Ángel Félix Gallardo in Narcos: Mexico.

Luna has appeared in numerous Mexican theatre productions and has produced both film and television projects, many of which feature Gael García Bernal. Since 2010, he has directed three feature films: Abel, Cesar Chavez, and Mr. Pig. He is the creator and director of the 2013 Fusion TV docu-series Back Home, the Amazon Studios talk show Pan y Circo, which premiered in 2020, and the 2021 Netflix scripted series Everything Will Be Fine. In 2025, Time magazine listed Luna as one of the world's 100 most influential people.