Generalized vitiligo is an acquired disorder in which patches of depigmented skin, overlying hair, and oral mucosa result from progressive autoimmune loss of melanocytes from the involved areas. Although vitiligo is perhaps the most common pigmentary disorder, insufficiently clear clinical definition of the disorder and lack of a good laboratory animal model have inhibited progress in understanding its pathobiology, its environmental triggers, and in developing specific and effective therapeutic approaches. Vitiligo results from a complex interaction of environmental, genetic, and immunologic factors, which ultimately contribute to melanocyte destruction, resulting in the characteristic depigmented lesions. In the past few years, studies of the genetic epidemiology of generalized vitiligo have led to the recognition that vitiligo is part of a broader, genetically-determined, autoimmune/autoinflammatory diathesis. Attempts to identify genes involved in vitiligo susceptibility have involved both allelic association studies of candidate genes and genome-wide linkage analyses to discover new genes, and these studies have begun to shed light on the mechanisms of vitiligo pathogenesis. It is anticipated that the discovery of biological pathways of vitiligo pathogenesis will provide novel therapeutic and prophylactic targets for future approaches to the treatment and prevention of vitiligo and its associated autoimmune diseases.