In 1981, Hernandez and his brothers Jaime and Mario published the first issue of Love and Rockets, which was quickly picked up by Fantagraphics Books, who republished the earliest materials in a new series starting in 1982. The magazine-sized comic book became known for its genre-bending, its punk-rock DIY ethic, and its multiracial (particularly Mexican-American) characters.

The first wider recognition of Gilbert and his brothers’ work occurred in 1982, after they had sent in a copy of their Love & Rockets comic, which up to that point they had been self publishing, to the Comics Journal, the foremost U.S. magazine of news and criticism pertaining to comic books and strips. This led to their work being published by the then just established Fantagraphics books. Between 1996 and 2001, the Love & Rockets series was temporarily suspended, while each brother, including Gilbert, pursued solo projects. During this time Gilbert created New Love, Luba, and Luba’s Comics and Stories. After its resumption, Love & Rockets continued to be published by Fantagraphics on an annual basis. In 2009, Gilbert published The Troublemakers, his second solo graphic novel with the publisher, inspired by pulp novels and heist films. This has continued a trend he started with Chance in Hell and Speak of the Devil; all three books are faux adaptations of fictional B-movies.

In 1983, Hernandez published the first part of the first Heartbreak Soup story in Love and Rockets #3. This began Palomar, Hernandez’ magic realist magnum opus which was completed in 1996. These stories take place in the fictional rural Latin American village of Palomar, where modern technology and rampant consumerism have yet to reach—or even phone lines. The focus on the stories was on the characters, with their variety of personalities, rather than on action as in superhero comics, or on shock value as in underground comix. Over the years, the Palomar stories became longer, more complex and more daring, especially in the long story “Human Diastrophism”, in which a serial killer appears in Palomar, whose identity is only known by an unstable artist who slowly loses his mind.

The first volume of Love and Rockets came to an end in 1996, with its fiftieth issue. Hernandez brought the Palomar stories to an end with a devastating earthquake, which briefly brings together many of the characters who had moved out of the village. The story closes with Luba and her family leaving for the United States to escape from hitmen. Jaime and Gilbert went their separate ways. Gilbert continued with Luba and her family in series such as Luba, Luba’s Comics and Stories, and edited to the children’s anthology Measles before its early demise.

In 2001, Love and Rockets returned with a second volume, published roughly quarterly. The new series was published in standard comic-book size, and in it Hernandez focused on shorter stories that didn’t rely on continuity. For his longer stories, he also began creating stand-alone graphic novels, such as Sloth (2006), about a teenager from a small town who wills himself into a coma.

The second volume of Love and Rockets came to an end after twenty issues. A third volume, called Love and Rockets: New Stories began in 2008. While Jaime continued with his Locas characters in the series, Gilbert focused on new characters.

Along with his brother Jaime, Gilbert has been named as one of Time’s “Top 100 Next Wave Storytellers” in 2009. He is also co-creator and co-star (with his wife, Carol Kovinick) of The Naked Cosmos, an eccentric low-budget TV show about a cosmic prophet known as Quintas.