All of the endemic mycoses have cutaneous and mucocutaneous manifestations that are most commonly seen when patients have disseminated infection. Biopsy of skin lesions is simple and safe and can assist in making a timely diagnosis of disseminated infection. Primary cutaneous inoculation infection has been reported with all of the endemic mycoses, but is rare. In this situation, a nodule or ulcer occurs at the inoculation site, is often accompanied by lymphangitis and regional lymphadenopathy, and systemic symptoms and signs as almost always absent. Mucosal lesions are common with disseminated histoplasmosis, but also have been described in patients who have disseminated blastomycosis and coccidioidomycosis. Biopsy is essential to rule out cancer and allows a rapid diagnosis of the endemic fungal infection.