Retinoids alone and in combination with interferon-alpha are the best systemic agents to study in the reversal of skin carcinogenesis and in the treatment of advanced squamous cell carcinoma of the skin. This article reviews the major laboratory advances in the mechanistic study of retinoids and interferons alone and in combination. Recent data in several cancer cell lines suggest that retinoic acid can potentiate the interferon signal-transduction pathway. Also reviewed is the current status of clinical studies of systemic retinoids and interferon in (i) skin cancer prevention (as single agents) and (ii) treatment of advanced squamous cell carcinoma (as single agents and in combination). Future clinical studies with translational laboratory correlates are necessary to determine the roles of retinoids and interferons in the prevention and treatment of skin cancer.