Cutaneous squamous cell carcinoma and basal cell carcinomas, commonly termed ‘nonmelanoma skin cancer’ or ‘epithelial skin cancers’, are among the most common cancers in white-skinned populations. The most prevalent risk factors that contribute to the pathogenesis of epithelial skin cancers include excessive exposure to UV radiation, pigmentary traits and genetic predisposition. A wide range of different treatment modalities have been used with the aim to eradicate the tumor while maintaining an acceptable cosmetic outcome. Surgical excision, Moh’s micrographic surgery, cryosurgery, curettage and electrodesiccation, radiotherapy, photodynamic therapy, as well as topical pharmacological agents (e.g., topical imiquimod, 5-fluorouracil) are currently employed, based on the individual tumor and patient characteristics. New insights into the pathogenesis of basal cell carcinomas and squamous cell carcinoma have led to the development of targeted treatments, such as hedgehog signaling pathway inhibitors, ornithine decarboxylase inhibitors, cyclooxygenase inhibitors and anti-EGF receptor inhibitors that are currently being tested for efficacy and safety in clinical trials. This review provides an up-to-date overview of novel and emerging systemic and topical treatments for epithelial skin cancers and discusses the rationale for their use in the evolving therapeutic landscape of these tumors.