Although the first immunotherapeutic agent approved for melanoma was interleukin-2, it was the blocker of negative regulators of T-cell activity, known as CTLA-4, that really expanded immunotherapy for melanoma, as it can lead to melanoma suppression. The starting data for CTLA-4 CTLA-4 showed no particular therapeutic benefit over interleukin-2, and follow-up trials showed an impressive 4-year survival rate of nearly 40% in previously untreated patients treated with high doses of CTLA-4 blockers. These data suggest that when most patients do not experience immediate tumor shrinkage, tumors may respond later in treatment, leading to prolonged survival. the CTLA-4 blocking antibody Ipilimumab (Yervoy) was approved in March 2011 for the treatment of melanoma. PD-1/PD-L1 PD-1 blockers can elicit responses in melanoma patients. In the phase I trial, the PD-1 inhibitor pembrolizumab (MK-3475) had a 34% complete remission rate. Preliminary evidence suggests that these responses are sustainable. Another phase I trial showed that the combination of the PD-1 inhibitor nivolumab and ipilimumab produced a response in 40% of patients. recent data on pembrolizumab and nivolumab were presented at the ASCO meeting in June 2014, and both classes of drugs are expected to eventually receive FDA approval. PD-L1 is a protein that binds and activates PD- 1 and is seen in many human tumors, including melanoma. By expressing PD-L1, tumors can suppress T cells that may enter the tumor and try to attack it. Several classes of PD-L1 antibodies have demonstrated promising results in clinical trials, with remission rates in excess of 20%. Thus, interfering with PD-1/ PD-L1 interactions appears to be more effective than CTLA-4 blockers and is likely to be a cornerstone of future melanoma therapy. T-VEC immune check inhibitor therapies have been very effective in melanoma treatment, but other strategies are also under active investigation and are coming to fruition. For example, lysozyme viruses are currently receiving increasing attention. The most cutting-edge drug in clinical trials is Talimogene laherparepvec (T-VEC). The phase III study of T-VEC presented at the 2014 ASCO Annual Meeting met the primary endpoint of remission rate (16% vs 2% control) and yielded a leading overall survival rate (P = .051). Intra-focal treatments such as T-VEC are likely to be part of future melanoma treatments and may enhance the activity of immune check blockers. In conclusion In conclusion, immunotherapy for melanoma has made great strides in the past 5 years. The diagnosis of metastatic melanoma is no longer a death sentence. The future of melanoma treatment may include combinations of different immunotherapies, including immune-checking blockers and in-lesion therapies, such as T-VEC. These immunotherapies may be combined in the future with targeted therapies, such as BRAF inhibitors, or with conventional treatments, such as radiotherapy. As part of the combination strategy, we will soon see new targets for immune activation including LAG-3, CD40, GITR, and OX-40.