During the past two years the CTLA-4 inhibiting antibody ipilimumab and the selective BRAF-inhibitor vemurafenib achieved significant improvements of overall survival for patients with non-resectable advanced melanoma. Remarkably, the targeting of BRAF and the inhibition of T cell activation blockade two differing mechanisms are active against melanoma and led to two approved agents in addition to chemotherapy. In 50 % of the patients melanoma mutated BRAF kinase is expressed and targeting with vemurafenib demonstrates rapid and reliable tumor responses. However, in most patients relapse during treatment due to the development of tumor resistance. The sustained BRAF-inhibitor sensitivity under treatment may be achieved by the combination with a MEK inhibitor. The antitumor effects of ipilimumab manifest later and response is harder to define since initial tumor progression or new lesions can precede tumor regression. Clinical trials employing combinations and further developments of these anti melanoma mechanisms will improve the situation of patients with melanoma in the future.