In 1985, Fresnadillo moved to Madrid. He started out in photography and cinema studies and then began his career in short films. In 1987, he set up a production company, which produced several short films and commercials. Fresnadillo went on to become a production assistant for Gustavo Fuertes' short film El juicio final (1991) (US title The Final Judgement 1991).
In 1996, he had his debut with the black-and-white short film Esposados (US title: Linked), for which he was also the executive producer. The black comedy tells the story of a couple who are constantly fighting over money; when they find themselves winning the Christmas lottery, however, they have such different ideas about what to do next that the husband tries to get rid of his wife. Esposados won 40 national and international awards. It was also nominated for an "Oscar" for Best Short Film in the same year, making Fresnadillo an overnight star in Spain.
In 2000, Fresnadillo was the presenter for the Goya Award in Best Short Film.
In 2002, Fresnadillo directed his debut full-length picture, the thriller Intacto. The film received several awards, most notably two 2002 Goya Awards (one of them for Fresnadillo in the category of Best New Director) and six further Goya nominations.
He then completed the 3-minute black-and-white picture Psicotaxi (2002), starring and portraying Alejandro Jodorowsky.
In 2006, he directed 28 Weeks Later, the sequel to Danny Boyle's 2002 film 28 Days Later (released in 2007).
