B-Raf^V600E inhibitors are potent at halting melanoma progression in patients harboring oncogenic B-Raf^V600E mutation. Recent studies indicate that chemotherapies and other target treatments suppress tumor growth via a host immunity-dependent manner. Using a genetically modified mouse model of melanoma, it was found that diminished CD40L- and IFNγ-mediated signaling contributed to the formation of immunosuppressive tumor microenvironment and that treatment with a Braf^V600E inhibitor, PLX4720, could reinvigorate local immune function. Indeed, maximal effectiveness of PLX4720 was dependent on restoration of CD40L- and IFNγ-mediated immune signals. This study illustrates that certain chemotherapies directed at the tumor rely on immune signaling pathways and that this has relevance for the design of combined treatments with immunotherapies. For details, see the article by Ho and colleagues on page 3205.