The article discusses the first major school of interpreter and translators in the New World, founded around 1533: the Imperial College of Santa Cruz de Tlatelolco. This college aimed at training native linguists with the capacity to perform a sort of spiritual crossbreeding, reconciling Renaissance humanism and Mesoamerican wisdom. The author describes the school's location and origin, the ideological background, as well as the students and teachers, their work, the problems encountered, the teaching orientation, etc. She emphasizes the permanent exchange of knowledge between natives an missionaries. Lost for centuries, the massive corpus of the translators and interpreters of the Imperial College of Santa Cruz de Tlatelolco has been recovered only recently.