Ramírez de Fuenleal, while Bishop of Santo Domingo, had encouraged the Franciscans to teach the sons of Indians grammar in their native language of Nahuatl.

Franciscan Arnaldo de Basccio had begun the task with considerable success, which gave support to the project of establishing an institute of higher learning.

Ramírez de Fuenleal had urged the crown to provide funds to establish and support such an institution.

The Franciscans had already established primary schools, one at Texcoco, established by Fray Pedro de Gante in 1523 and the other by the leader of the First Twelve Franciscans, Martín de Valencia in Mexico-Tenochtitlan in 1525.

Still others had been founded by Franciscans in this early period.

These schools for Indian and mestizo boys taught basic literacy, but also singing, instruction in how to help with the mass, and sometimes manual labor.

The primary education of Indian girls was also a concern and schools were established in Mexico City, Texcoco and six other locations lasting only for a decade.

However, not until the establishment of the Colegio de Santa Cruz de Santiago Tlatelolco, the first seminary in the New World, are sons of Indian men given higher education.

Bishop Zumárraga is a supporter of the establishment of the colegio, but credits Fuenleal and the crown for the accomplishment.

The colegio is inaugurated on January 6, 1536, the feast of the Epiphany, deliberately chosen for its symbolism of calling the gentiles to the true faith.

The establishment of such a school to train young men for the priesthood is highly controversial, with opposition especially coming from Dominican friars and articulated by the head of that order, Fray Domingo Betanzos.

Franciscan Bernardino de Sahagún writes a strong defense of the capacity of the Indians, countering the opinions of those who doubted the Indians' ability not only to learn Latin grammar, but to speak, and compose in it.

He goes on to refute concerns about the possibility of the Indians spreading heresy.

Betanzos in his opposition to the colegio says that Indians who know Latin could expose the ignorance of (European) priests, an argument that perhaps unwittingly exposes the flaws of the existing clergy.

The original purpose of the colegio is to educate a male indigenous priesthood, so pupils are selected from the most prestigious families of the Aztec ruling class.

These young men are taught to be literate in Nahuatl, Spanish and Latin, and receive instruction in Latin in music, rhetoric, logic, and philosophy, and indigenous medicine.

One student educated at the colegio is Nahua botanist Martín de la Cruz, who in 1552 will write the Libellus de Medicinalibus Indorum Herbis, an illustrated herbal.

Actual instruction at the colegio is by two Franciscans at a time, aided by Indian assistants.