Melanoma is a highly malignant tumor derived from skin melanocytes (pigment-producing cells), which is associated with a significant rate of systemic metastases and death. Various therapeutic approaches for melanoma have been attempted in recent years, including the use of chemotherapy, immunotherapy, and ablative surgical and radiation treatments. However, in many cases these treatments fail as the tumor becomes resistant to the treatment and rapidly spreads and causes death. Reports in the medical literature have documented the unique immunogenic nature of melanoma where antigens, antibodies, and immune complexes seem to play a major role in the course of the disease. Anti-melanoma antibodies can cross-react with antigens on normal melanocytes, therefore causing the appearance of an associated hypopigmentation that resembles vitiligo. Vitiligo is a dermatological disorder characterized by local, dispersed, or diffuse white patches on the skin as a result of the destruction of melanocytes. This disease is believed to be an autoimmune disorder since autoantibodies against membrane components of melanocytes are found in the sera of patients with vitiligo. Melanoma triggers an anti-tumor response in many patients. Unfortunately, such anti-tumor response is insufficient to elicit tumor regression and the tumor continues to proliferate. Since the prognosis of melanoma in patients and animals with vitiligo is more favorable than in the general population, it was hypothesized that sera from patients with vitiligo may react against melanoma cells. Such studies have demonstrated that exposure of tumor cells to the sera resulted in inhibition of proliferation of the melanoma cells in vitro and in regression of melanoma metastases in mice presumably on account of the presence of the high titer of anti-melanoma antibodies in the sera used in these studies. In this review we discuss the known data and hypothetical assumptions related to the use of vitiligo-associated antibodies against melanoma, as well as characterize the immune mechanisms involved in this process.