Mutations activating the receptor tyrosine kinase c-Kit occur commonly in melanomas arising on mucosal membranes and acral skin. Clinical studies have demonstrated that selective inhibition of c-Kit is effective in treating patients with c-Kit mutant gastrointestinal stromal tumors, but c-Kit inhibitor activity has been disappointing in c-Kit mutant melanoma patients. Activated c-Kit utilises phosphatidylinositol 3-kinase (PI3K) signalling as the dominant effector of cell proliferation and survival with the mitogen-activated protein kinase (MAPK) cascade serving as an ancillary survival pathway. We confirmed that these pathways are re-activated in melanoma cells with acquired resistance to c-Kit inhibitors and that these resistant sublines remain sensitive to the concurrent inhibition of MAPK and PI3K signalling. These findings suggest that durable responses in c-Kit mutant melanoma may require combination therapies that selectively inhibit critical downstream proliferative and survival pathways. We also discuss the interaction between targeted therapies and anti-tumor immune responses and the need to consider immunotherapies in new combinatorial treatment approaches.