Merkel cell carcinoma (MCC) is a skin cancer with 30% mortality and an incidence that has tripled in the past 15 years. There is agreement that surgical excision with negative margins is an appropriate therapeutic first step and that sentinel lymph node biopsy is a powerful prognostic indicator. After excision of detectable cancer, optimal adjuvant therapy is not well established. A role for adjuvant radiotherapy is increasingly supported by observational data. These data suggest that a regimen of surgery plus adjuvant radiotherapy is associated with both a lower loco-regional recurrence rate and longer overall survival when compared with surgery alone. In contrast, a role for adjuvant chemotherapy is not well supported. The rationale for chemotherapy in this disease is based on small-cell lung cancer, a more common neuroendocrine tumor for which chemotherapy is the primary treatment modality. Several issues call into question the routine use of adjuvant chemotherapy in MCC: lack of evidence for improved survival; the associated morbidity and mortality; important differences between small-cell lung cancer and MCC; and rapid development of resistance to chemotherapy. Importantly, chemotherapy suppresses immune function that plays an unusually large role in defending the host from the development and progression of MCC. Taken together, these arguments suggest that adjuvant radiation may be indicated for many MCC patients while adjuvant chemotherapy should largely be restricted to clinical trials.