Melanoma incidence is increasing annually and over 40,000 die of this disease each year worldwide. In this review, we discuss the rationale and recent trial results of several novel immunotherapeutic approaches and small molecule inhibitors of signalling kinases. Ipilimumab is a humanized anti-CTLA4 antibody that has been proven to increase the median overall survival of large cohorts of patients with unresectable melanoma in two phase III trials. OncoVEX(GM-CSF) is an oncolytic herpes simplex virus-1 recombined with granulocyte-macrophage colony-stimulating factor that has demonstrated durable objective responses in a phase II trial. Tumour-infiltrating lymphocytes given after lymphocyte depletion and followed by high-dose interleukin (IL)-2 yield durable complete responses in a significant percentage of melanoma patients. Lastly, denileukin diftitox, a fusion of IL-2 and diphtheria toxin, was recently observed to deplete regulatory T cells and cause durable partial responses, particularly in chemo/immune-naïve patients. These agents are enabling the rational design of novel combination trials to simultaneously increase antigen presentation, deplete regulatory T cells and block immune check-points in order to activate melanoma antigen-specific immunity. Although melanoma metastases have been found to contain thousands of mutations, the V600E BRAF mutation is clearly a driver of the neoplastic phenotype and is present in 40-60% of melanomas. Two separate small molecule antagonists of B-Raf have been found to yield very high partial response rates in metastatic melanoma, and the B-Raf inhibitor, vemurafenib (PLX4032), was recently observed to increase median overall survival in an interim analysis. However, B-Raf inhibitor resistance through up-regulation or activating mutations of alternative oncogenic signalling receptors and enzymes is proving to be a major challenge. Inhibitors of c-Kit and mitogen-activated protein kinase (MEK) have also been found to have activity against melanomas and MEK inhibitors are now being examined as a strategy to overcome B-Raf inhibitor resistance. In summary, these studies reveal that, for the first time, several immunotherapeutic and targeted agents are yielding dramatic clinical responses and improvements in overall survival in patients with unresectable stage III and IV melanoma.