In recent years, therapeutic approaches for many tumors have broadened or even shifted entirely from cytotoxic chemotherapy to specific targeting of dysregulated proteins (predominately kinases), and more recently, harnessing of the anti-tumor immune response. The most prominent example of this shift is the management of metastatic melanoma, where BRAF and MEK inhibition and CLTA-4 blockade have established an entirely new standard of care in the last 3 years. Targeted kinase inhibition and immune checkpoint blockade have different strengths and weaknesses. Kinase inhibitors generally have rapid and impressive response rates but modest progression-free survival while immunotherapy can achieve durable tumor control, but is often associated with lower response rates and slower time to clinical benefit. These approaches would seem to be complementary however the results of early combination studies suggest that caution is advised when combining targeted kinase inhibition with immunotherapy. In this context, rigorous biomarker driven clinical trials are needed to further elucidate mechanisms of both benefit and toxicity. Depending on disease specific biology, it seems likely that both combination and sequential approaches of kinase inhibitors with immunotherapy will be required in order to harness the full potential of these approaches.