This article presents some of the authors' perspectives on the past 20 years of work that applies the results of research in historical linguistics to the understanding of the histories and cultural practices of pre-Columbian Mesoamericans. It focuses on major cultural transformations to which both historical linguistic and archaeological data can contribute, such as the spread of agriculture, and migrations in Mesoamerican prehistory. It also addresses major culture-historical studies on narrower topics: on Nawa and its place in the prehistory of Mexico, in particular confirming standard views that Nawas were immigrants into Mesoamerica; on Archaic and Formative period interactions involving Oto-Mangeans, which is work that is largely still to be done; on the prospects for work on long-distance contacts between Mesoamerica and North America; on the contributions of historical linguistics in Mesoamerican epigraphy; and on the value and prospects of updating the methodology of glottochronology.