A common treatment modality for in transit melanoma of the extremity has been hyperthermic isolated limb perfusion (HILP) with melphalan and more recently, isolated limb infusion (ILI) with melphalan with or without dactinomycin. Research in the area has primarily focused on maximizing drug delivery through a better understanding of pharmacokinetics while maintaining acceptable levels of toxicity. Although other agents continue to be explored as regional chemotherapy agents, melphalan is currently the drug of choice, although temozolomide has demonstrated promising preclinical results. Resistance mechanisms to melphalan and melphalan pharmacokinetics are studied using animal models of HILP and ILI. The addition of modulators to overcome resistance to the traditional chemotherapy regimen may ultimately improve the clinical response in patients with in-transit melanoma of the extremity.