Romero was named National Artist of the Philippines in 2003, and his body of work delved into the history and politics of his country. His 1976 film Ganito Kami Noon…Paano Kayo Ngayon?, set at the turn of the 20th century during the revolution against the Spaniards and, later, the American colonizers, follows a naïve peasant through his leap of faith to become a member of an imagined community. Agila situated a family’s story against the backdrop of Filipino history, while Kamakalawa explored the folklore of prehistoric Philippines. Banta ng Kahapon, his "small" political film, was set against the turmoil of the late 1960s, tracing the connection of the underworld to the corrupt halls of politics. His 13-part series Noli Me Tangere brought Philippine national hero José Rizal's novel to a new generation of viewers.
Along with Filipino-language films, he made English-language films that became cult classics, like Black Mama, White Mama and The Twilight People and worked with American actors like John Ashley and Pam Grier. Romero's films, the National Artist citation stated, "are delivered in an utterly simple style – minimalist, but never empty, always calculated, precise and functional, but never predictable." Quentin Tarantino drew on Twilight People as an inspiration for his "grindhouse" homages.
Married to Carol Gonzalez, Romero was for a time the partner of actress Mila del Sol. He died of a blood clot and prostate cancer on May 28, 2013. He was survived by three children. Romero was an alumnus of Silliman University.