Skin cancers are considered advanced when they are observed to spread aggressively, demonstrate resistance to multiple treatments, or readily recur. These include those that are locally advanced and/or metastatic. Treatment regimens may include excision with or without sentinel lymph node biopsy or neck dissection, Mohs surgery, radiation therapy, chemotherapy, or immunotherapy, either alone or in combination. Surgery remains the mainstay of treatment for early-stage disease of all skin cancer types and may comprise one of multiple treatment modalities for more advanced disease. Advances in reconstruction have expanded our ability to restore form and function. The role of radiation therapy is often adjuvant and dependent on tumor type, extent, and cervical nodal disease. A myriad of new medical treatments has emerged which target specific mutations or harness facets of the immune system. As such, it is more critical than ever for the otolaryngologist to understand current treatment algorithms, the role of the immune system in emerging treatment paradigms, the mutational landscape that generates targeted therapy, and future directions of current research. This course will focus on 4 main skin cancer subtypes: melanoma, merkel cell carcinoma, squamous cell carcinoma, and basal cell carcinoma. We will highlight the similarities and differences in treatment approach based on pathology and extent of disease. A case-based format will be utilized to discuss the role of local therapies including surgery, reconstruction, and radiation and systemic therapies. A focused discussion of clinically applicable biomarkers, mutation testing, emerging systemic treatments, and current research will provide a framework for the otolaryngologist to treat and counsel patients.