Melanoma has a wide spectrum of histologic features which mimic epithelial, hematologic, mesenchymal, and neural tumors. Immunohistochemistry has been the primary tool to distinguish melanomas from these other tumors; it has also been studied for use as an adjunct to distinguish benign and malignant melanocytic tumors and to elucidate prognosis. Furthermore, there has been extensive effort to find a suitable marker to differentiate spindle cell and desmoplastic melanoma from other tumors. We have reviewed the literature investigating melanocytic differentiation markers, proliferation markers, immunomodulatory markers, signaling molecules, and nerve growth factors and receptors. Despite the proliferation of immunohistochemical markers, S-100 remains the most sensitive marker for melanocytic lesions, while markers such as HMB-45, MART-1/Melan-A, tyrosinase, and MITF demonstrate relatively good specificity but not as good sensitivity as S-100. No marker has proven useful in distinguishing spindle cell and desmoplastic melanomas from other tumors. Ki67 remains the most useful adjunct in distinguishing benign from malignant melanocytic tumors. None of the markers reviewed has been shown conclusively to have prognostic value for melanocytic neoplasms.