Tooth crown lengths, breadths, and areas were compared from five sequential human skeletal samples from the Valley of Oaxaca, Mexico, spanning the period from 1600 BC to AD 1521. Almost all of the measurements considered exhibited dramatic reduction over that period. Total crown area declined from 1320 mm2 to 1262 mm2, a change of 4.4% or 9.4 darwins, which is noticeably larger than any previously reported rate of dental reduction in a recent human population. This reduction was greatest in posterior tooth breadths, especially in the mandible. The patterning of the reduction, and of the variance of the measurements, indicates that natural selection was primarily responsible for the change. Of all the measurements, anterior breadths appear to have been the least subject to selection, and posterior lengths the next least. The degree of reduction suggests that selective pressures towards smaller teeth were greater in Mesoamerica than elsewhere. This case provides an example of the value of recent human skeletal series for the study of microevolutionary processes.