Two longstanding literate worlds, Spanish and Mesoamerican, met and remade each other as part of colonial encounters. The 2012 International Workshop on Indigenous Literacy in Mesoamerica and the Colonial World at the John Carter Brown Library (JCB) at Brown University hosted a diverse group of scholars to debate the social consequences of colonial Mesoamerican literacy. This issue of Ethnohistory is the result of that productive interaction. Comparing highland and lowland Mayan, Mixtec, central Mexican Nahuatl, and southern Nahua (Pipil) literacy from the Late Postclassic (AD 1200–1521) to the present day reveals commonalities as well as regional, and even individual, variation in the form, method, and consequences of literate practices. Investigating literacy allows us to move beyond debates about what constitutes writing per se and instead recognize that inscribing, no matter the method, was part of a sustaining environment of literacy that gave expressive practices their relevance and value in colonial Mesoamerica.