The present study consists of two major parts: the first and central part of the project is an expanded historical and cultural consideration of Luis Venegas de Henestrosa’s Libro de cifra nueva (1557); the second is a translation of Venegas’s Libro, here made available in English for the first time. As one of the earliest books of intabulations for keyboard printed in Spain, the Libro is a valuable source of information about keyboard practice in 16th-century Spain: performance practices, improvisation at the keyboard, the repertoire played on and arranged for the instrument, and the sources of that repertoire. The project places this important source in the context of Early Modern Spanish culture and addresses important shifts in music pedagogy arising from by Humanist ideas introduced to Spain in the 16th century. My study shows that autodidacticism (or self-teaching) was the Humanist ideal that had the most impact on the content and layout of the book. Given the great degree of self-determination that this book’s autodidacticism offered readers, its musical praxis stands revealed as an important socio-cultural tool. Drawing on other contemporary works that promote the use of autodidacticism to learn language, decorum, games, and court polity, my conclusions show how music-making could become a powerful set of skills capable of shaping subjectivity, a set of skills that was used equally by individual subjects as well as the State in the process of creating identity.