Traditionally, four groups of factors have been identified in the etiology of temporomandibular disorder (TMD): anatomical variation in the masticatory system; psychosocial characteristics; pain in other body regions; and demographics. Orthodontic treatment has been variously cited both as a protective and harmful factor in TMD etiology. Recently, a search has begun for a genetic influence on TMD etiology. Genetic markers can be of additional value in identifying gene-environment interactions, that is, isolating population sub-groups, defined by genotype in which environmental influences play a relatively greater or lesser etiological role. This paper reviews concepts and study design requirements for epidemiological investigations into TMD etiology. Findings are presented from a prospective cohort study of 186 females that illustrate an example of gene-environment interaction in TMD onset. Among people with a variant of the gene encoding catechol-O-methyl-transferase, an enzyme associated with pain responsiveness, risk of developing TMD was significantly greater for subjects who reported a history of orthodontic treatment compared with subjects who did not (P=0.04). While further studies are needed to investigate TMD etiology, this genetic variant potentially could help to identify patients whose risk of developing TMD is heightened following orthodontic treatment, hence serving as a risk marker useful in planning orthodontic care.