Treatment of recurrent or in-transit unresectable melanoma continues to be a major therapeutic challenge. Electrochemotherapy (ECT) is a therapeutic option for those patients whose lesions are not suitable for surgical resection and who have exhausted all other treatment modalities. ECT combines electroporation of tumor cells with the administration either of intravenous or intratumoral antineoplastic drugs, such as bleomycin or cisplatin. The cell membranes are thus rendered permeant to these impermeant hydrophilic drugs with a several hundred-fold increase in intracellular delivery and cytotoxicity. ECT is an effective treatment in the palliative management of unresectable recurrent disease with overall objective response rates of approximately 80-90%. ECT technology continues to evolve allowing application to deeper lesions. By combining ECT with tumor-specific immunostimulating approaches, such as perilesional IL-2, CpG oligonucleotides or prior immunogene therapy, there is a promise of both local and systemic control of this disease.