Skin cancer is highly curable under most circumstances; however, locally advanced or metastatic disease historically has poor outcomes and limited treatment options. Treatment has recently been advanced by the discovery of pertinent genes influencing pathogenesis and further revolutionized by the advent of specific gene expression profiles (GEPs). GEPs have been developed to help refine current diagnostic and prognostic strategies used in skin cancer with the goal to ultimately help guide management and treatment modalities to improve patient care. This article provides a high-level review of diagnostic and prognostic GEPs that have been developed specifically for squamous cell carcinoma and melanoma.