Clinically detectable regional lymph node melanoma metastasis (AJCC stage IIIB-C) carries a risk of relapse and death that approaches 70% at 5 years. Surgical management is the cornerstone of therapy, with postoperative adjuvant therapy utilizing high-dose interferon alfa-2b (HDI). Neoadjuvant chemotherapy or immunotherapy in addition to surgery has been demonstrated to improve outcome in the management of patients with a variety of solid tumors. In patients with melanoma, the characteristics of the host immune response differ between patients with earlier stage and those with more advanced stages of disease (and particularly between those with measurable active disease and those without measurable gross disease) providing rationale for neoadjuvant approaches with immunotherapy. Host immune tolerance is now understood to impede the results of therapy for advanced disease, but appears to be less an issue for patients with microscopic high-risk operable disease, where the host may be more susceptible to immunologic interventions. Phase II studies have shown that neoadjuvant biochemotherapy has limited activity in melanoma patients with local-regional metastases, where chemotherapy may potentially alter the effects of immunotherapeutic agents. Studies of neoadjuvant HDI therapy for high-risk melanoma patients with bulky regional stage IIIB-C lymphadenopathy have shown unexpectedly high clinical and pathologic response rates, without increased morbidity. Through the design of neoadjuvant trials utilizing promising emerging melanoma therapeutics in which it is possible to obtain biopsy samples before and after therapy, a greater understanding of the dynamic interaction between tumors and the immune system is possible. This should lead to the identification of new targets for the treatment of melanoma and aid the development of new immunotherapy that may have greater specificity and less toxicity. This will simplify the evaluation of promising new combinations of agents with HDI to build on the clinical, immunologic, and molecular effect of this therapy for patients with melanoma.