Treatment of metastatic melanoma was radically changed by the introduction of inhibitors of BRAF, an oncogene mutated in 40-50% of patients. Another area of advancement was the use of immunotherapy, and specifically, immune checkpoint inhibitors. There is compelling evidence that oncogenic BRAF, in addition to driving melanoma proliferation, differentiation and survival, induces T-cell suppression directly through the secretion of inhibitory cytokines or through membrane expression of co-inhibitory molecules such as the PD-1 ligands PD-L1 or PD-L2. Furthermore, the presence of oncogenic BRAF leads to an immune suppressive phenotype characterized by the presence of inhibitory immune cells such as regulatory T cells, myeloid-derived suppressor cells, or tumor-associated macrophages, which can in turn inhibit the function of tumor-infiltrating T cells. Growing evidence suggests that, in addition to their established molecular mechanism of action, the therapeutic efficacy of BRAF inhibitors and MEK inhibitors relies on additional factors that affect the tumor-host interactions, including the enhancement of melanoma antigen expression and the increase in immune response against tumor cells. Focus of the present review is to summarize the off target mechanisms of response to BRAF inhibitors and MEK inhibitors and the synergy between targeted therapy and immunotherapy as the biological source to open a window of strategic opportunities for the design of new exciting clinical trials.