This essay compares the theological orientation of Bartolomé de Las Casas (1484–1566) with those of two other notable colonial Latin American ecclesial figures: Toribio de Benavente Motolinía (1494/95–1565), and Juan Vasco de Quiroga (1477/78–1565). An examination of the experiential and theoretical epistemological sources of their theological orientations reveals the influence of different temporal, social, and geographic experiences as well as of their common and distinctive intellectual formations. Their understandings of and activities in the New World reflect these epistemological influences. The data demonstrate that Las Casas’s theological orientation was primarily prophetic in his quest for justice for the Indigenous and drew from Thomism and Scripture; Motolinía’s was predominantly millenarian in his ardor to establish the New Jerusalem and mirrored the Franciscan Spirituals’ tradition; Quiroga’s was principally utopian in his approach to Christianize, civilize, and educate the Indigenous as well as employed Christian humanist ideas. A summary analysis argues that the prophetic dimension of Las Casas’s theological orientation is further differentiated from that of his two contemporaries by its universalist character and its dynamic development during the course of his lifetime.