In-transit melanoma represents a distinct disease pattern in which melanoma recurs as dermal or subcutaneous nodules between the primary melanoma site and the draining regional lymph node basin. The disease pattern is often not amenable to complete surgical resection. Since the 1950s, regional therapies have been explored for the treatment of this disease entity, with the goal of maximizing delivery of the therapeutic agent to the tumor while minimizing systemic toxicity. We reviewed landmark studies describing and evaluating regional chemotherapy and intralesional therapies for patients with in-transit melanoma metastases.