In-transit metastases for melanoma are a type of stage III regional metastatic disease that are intradermal or subcutaneous nodules growing within lymphatics and not in nodal basins. If the initial diagnosis is a limited number of in-transit metastases (1-3 nodules), the optimal management is simple surgical excision with minimal negative margins and primary closures and appropriate staging to look for any distant metastases. There is no role for wide excision of in-transit lesions as there is for primary melanoma because the entire extremity or that region of the body is at risk for recurrence. Patients who are diagnosed with additional lesions in a short period of time or patients who at initial diagnosis have large numbers of nodules are candidates for isolated limb perfusion (ILP). ILP is a regional administration of high-dose chemotherapeutics within an extremity using a cardiopulmonary bypass machine similar to cardiac surgery. Once isolation is obtained surgically, the limb is heated to what is considered mild hyperthermia (38.5 degrees -40 degrees C), then chemotherapeutics are administered at very high concentrations for a 60- to 90-minute treatment. The drug recirculates and, at the end of the treatment period, it is flushed from the extremity and the circulation is re-established. The optimal regimen is melphalan dosed per limb volume (10 mg/L limb volume for lower extremities and 13 mg/L limb volume for upper extremities) with mild hyperthermia for 60 minutes. Using this regimen, overall response rates between 80% and 90% and complete response rates between 55% and 65% can be obtained. The duration of response is typically 9 to 12 months and a subgroup of complete responders, which is 20% to 25% of the total patient population, typically have sustained complete responses. The major toxicities are skin erythema, myopathy, and peripheral neuropathy. There have been several studies adding high-dose tumor necrosis factor to ILP, but there is no clear benefit in the treatment of melanoma. Other new approaches include isolated limb infusion as a percutaneous procedure to avoid the surgical toxicity.