The article provides a comprehensive overview of therapeutic approaches for non-melanoma skin cancers (NMSCs), including cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), and Merkel cell carcinoma (MCC). UV radiation is the leading risk factor for NMSCs, and immune suppression exacerbates the risk and aggressiveness of these cancers. Surgical excision remains the most common treatment, but it is less effective for advanced or metastatic disease. Recent advancements in pharmacological targets and immunotherapy have led to the development of novel treatments. Hedgehog pathway inhibitors are effective for advanced and metastatic BCC, while PD-1/PD-L1 inhibitors are beneficial for locally advanced cSCC and MCC. Despite the efficacy of these new drugs, drug resistance and tolerability issues often arise. Ongoing studies aim to identify alternative strategies with reduced adverse effects and increased tolerability. The review also discusses the pathogenesis of NMSCs, the clinical features and staging of each type, and the current and emerging therapies available. Future perspectives highlight the need for a holistic approach that addresses the complex interactions within the tumor microenvironment and the evolving nature of cancer cells.The article provides a comprehensive overview of therapeutic approaches for non-melanoma skin cancers (NMSCs), including cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), and Merkel cell carcinoma (MCC). UV radiation is the leading risk factor for NMSCs, and immune suppression exacerbates the risk and aggressiveness of these cancers. Surgical excision remains the most common treatment, but it is less effective for advanced or metastatic disease. Recent advancements in pharmacological targets and immunotherapy have led to the development of novel treatments. Hedgehog pathway inhibitors are effective for advanced and metastatic BCC, while PD-1/PD-L1 inhibitors are beneficial for locally advanced cSCC and MCC. Despite the efficacy of these new drugs, drug resistance and tolerability issues often arise. Ongoing studies aim to identify alternative strategies with reduced adverse effects and increased tolerability. The review also discusses the pathogenesis of NMSCs, the clinical features and staging of each type, and the current and emerging therapies available. Future perspectives highlight the need for a holistic approach that addresses the complex interactions within the tumor microenvironment and the evolving nature of cancer cells.