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Throughout his career, del Toro has shifted between Spanish-language films—such as Cronos (1993), The Devil's Backbone (2001), and Pan's Labyrinth (2006)—and English-language films, including Mimic (1997), Blade II (2002), Hellboy (2004) and its sequel Hellboy II: The Golden Army(2008), Pacific Rim (2013), Crimson Peak (2015), The Shape of Water (2017), Nightmare Alley (2021), and Pinocchio (2022).

As a producer or writer, he worked on the films The Orphanage (2007), Don't Be Afraid of the Dark (2010), The Hobbit film series (2012–2014), Mama (2013), The Book of Life (2014), Pacific Rim: Uprising (2018), Scary Stories to Tell in the Dark (2019), and The Witches (2020). In 2022, he created the Netflix anthology horror series Guillermo del Toro's Cabinet of Curiosities, featuring a collection of classical horror stories.

With Chuck Hogan, he co-authored The Strain trilogy of novels (2009–2011), which was later adapted into a comic book series (2011–15) and a live-action television series (2014–17). With DreamWorks Animation and Netflix, he created the animated franchise Tales of Arcadia, which includes the series Trollhunters (2016–18), 3Below (2018–19), and Wizards (2020) and the sequel film Trollhunters: Rise of the Titans (2021).

Del Toro is close friends with fellow Mexican filmmakers Alfonso Cuarón and Alejandro G. Iñárritu, collectively known as "The Three Amigos of Mexican Cinema". He has received several awards, including three Academy Awards, three BAFTA Awards, two Golden Globe Awards, a Daytime Emmy Award, and a Golden Lion. He was included in Time magazine's list of the 100 most influential people in the world in 2018, and he received a motion picture star on the Hollywood Walk of Fame in 2019.