Melanomas are among the most common skin tumors in horses, with prevalence rates reaching as high as 80% in adult gray horses. Most melanocytic tumors are benign at initial presentation; however, if left untreated, up to two-thirds can progress to overt malignant behavior. Standard local treatment options can be used to treat solitary early-stage lesions but do not address the underlying risk of recurrent tumor formation or the transformation to a malignant phenotype. An understanding of the specific molecular genetic factors associated with tumor formation should lead to targeted therapies that can be used to treat or ideally prevent disease.