Vitiligo reflects a systemic process that has important implications beyond the skin. These include other autoimmune diseases and ocular and neurological abnormalities. Alezzandrini syndrome and Vogt-Koyanagi-Harada syndrome particularly exemplify this relationship. In addition, vitiligo may be confused with other systemic disorders, including tuberous sclerosis, progressive systemic sclerosis (scleroderma), melanoma, and, in endemic regions, leprosy. We describe these associations and emphasize the importance of depigmenting disorders.