An appropriate biopsy is the pivotal procedure that facilitates accurate histopathologic diagnosis of a pigmented skin lesion. Excisional skin biopsy is the method of choice for removing a suspected malignant melanoma. More than 95% of malignant melanomas that involve the skin belong to one of the four most common clinicopathologic categories: superficial spreading, nodular, lentigo maligna, and acral lentiginous melanoma. A small but important group of cutaneous melanomas can be classified as unusual variants. Many of these unusual variants have a distinct histopathologic appearance; they include desmoplastic melanoma, neurotropic melanoma, pedunculated melanoma, metastatic melanoma, amelanotic melanoma, melanoma arising within a benign nevus, regressing ("invisible") melanoma, and balloon cell melanoma. Other lesions may simulate malignant melanoma histopathologically. Immunohistochemical stains, such as S-100 protein, vimentin, keratin, and HMB-45, are useful for distinguishing these lesions from true melanoma.