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He gained his doctorate in Comparative Literature at Harvard. He held the post of Professor of Comparative Literature at the universities of San Diego, California, Princeton and Harvard between 1978 and 1985. He is now Emeritus Professor of Harvard University, the Autonomous University of Barcelona and Pompeu Fabra University. He left Spain at a very early age (1939) and embarked on a long exile with his father, the poet Jorge Guillén, who awoke his interest in literature and poetry. After lecturing at the above-mentioned North American universities, he returned to Spain in 1982. In the same year, he was named extraordinary Professor of Comparative Literature by the Autonomous University of Barcelona, a field in which he is regarded as a great specialist and pioneer in Spain. He is the author of works about the subject he has always promoted, comparative literature. Guillén has also worked in the publishing world, editing the following collections: ‘Clásicos Alfaguara', ‘Escritores de América' and ‘La Biblioteca de Literatura Universal' (Espasa Calpe). He was the critical editor of the work De Garcilaso a Lorca, by Francisco García Lorca. He was president, between 1984 and 1989, of the Spanish Society of General and Comparative Literature, and is now a member of the International Society of Comparative Literature and of the Advisory Commission of the Fundación Juan March. On 23 March 2002 he was chosen as a scholar of the Spanish Royal Academy.

He has written the following books: Los pleitos extremeños de Mateo Alemán: I El Juez, ‘Dios de la tierra' (1960); The Anatomies of Roguery: a Comparative Study in the Origins and the Nature of Picaresque Literature (1967); Literature as System: Essays toward the Theory of Literary History... (1971); Entre lo uno y lo diverso: introducción a la literatura comparada (1985); El Primer Siglo de Oro: estudios sobre géneros y modelos (1988); Teoría de la historia literaria (1989); La expresión total: notas sobre literatura y obscenidad (1993); El sol de los desterrados (1995); Europa, ciencia e inconsciencia (1997), Múltiples moradas (1998) and Entre el saber y el conocer: moradas del estudio literario (2001).