After graduating in Rome in 1957, Portoghesi becomes one of the first architects to pit himself against functional rationalism both with his studies on Guarino Guarini and Francesco Borromini, and the surprising Casa Baldi in Rome (1959) where he unites the Avant-Garde and Baroque.
His Rome Mosque(1975-1993) is the high point of his research. He is the curator of the First Venice Architecture Biennial, (1980) and director of the Strada Novissima installation. Portoghesi is one of the key characters in the post modern movement.
He has been the director of the magazines Controspazio, Eupalino, Materia and Abitare la Terra. He has taught at the School of Architecture of Rome and Milan, where he is also Dean from 1968 to 1977.