Dental reduction has been sufficiently widespread among human populations to render the phenomenon of reduced tooth size worthy of scientific explanation. One of the most controversial models invoked to explain structural reduction in organisms is referred to as the “probable mutation effect” (PME). According to this model, structures no longer functional owing to ecological or cultural changes will experience a relaxation of selection pressure, permitting an accumulation of mutations in the population that inevitably will result in the reduction in size or the loss of the concerned structure. Although the PME continues to be offered as a viable explanation of human dental reduction, it is based upon several premises that modern dental clinical experience fails to support. Known enzyme defects resulting from mutations, factors predisposing to dental infections, and the deleterious effects of teeth that are too large or too small reveal that the PME does not logically account for the reduction of tooth size. Given such information, this paper proposes models of dental reduction based upon natural selection, which, unlike the PME, are testable in both modern and archaeological populations. The integration of clinical and skeletal data permits a more thorough understanding of dental reduction in the hominid fossil record.