The incidence of malignant melanoma is increasing faster than any other cancer. In cases of recurrent melanoma confined to the extremities, hyperthermic isolated limb perfusion and isolated limb infusion provide a way to isolate the extremity and deliver a dose of chemotherapy several orders of magnitude higher than would be tolerated systemically. Although complete response rates of up to 80% for hyperthermic isolated limb perfusion and 44% for isolated limb infusion have been observed, there is still room for improvement and standardization in these two procedures in an attempt to optimize response while minimizing toxicity. Currently, new chemotherapy agents and small-molecule inhibitors are being investigated as a means of overcoming chemoresistance and improving response rates. In patients with advanced cutaneous disease confined to the extremities, evaluation of these new therapies can be very informative, as tissue acquisition at multiple treatment time points is easy owing to the superficial and multifocal nature of the disease. Through studying the biomolecular and genetic alterations in tumor tissue in response to these new therapies, genetically customized treatment regimens in which tumor resistance and sensitivity is predicted and treatment strategy is optimized before treatment begins may soon be available. Progress in regional therapy will prove not only beneficial for patients with disease confined to an extremity, but may also provide insight into developing novel treatment strategies for patients with systemic disease for whom current disease management options are poor.