Recent breakthroughs in the treatment of advanced melanoma are based on 
scientific advances in understanding oncogenic signaling and the immunobiology 
of this cancer. Targeted therapy can successfully block oncogenic signaling in 
BRAF(V600)-mutant melanoma with high initial clinical responses, but relapse 
rates are also high. Activation of an immune response by releasing inhibitory 
check points can induce durable responses in a subset of patients with melanoma. 
These advances have driven interest in combining both modes of therapy with the 
goal of achieving high response rates with prolonged duration. Combining BRAF 
inhibitors and immunotherapy can specifically target the BRAF(V600) driver 
mutation in the tumor cells and potentially sensitize the immune system to 
target tumors. However, it is becoming evident that the effects of paradoxical 
mitogen-activated protein kinase pathway activation by BRAF inhibitors in 
non-BRAF-mutant cells needs to be taken into account, which may be implicated in 
the problems encountered in the first clinical trial testing a combination of 
the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant 
liver toxicities. Here, we present the concept and potential mechanisms of 
combinatorial activity of targeted therapy and immunotherapy, review the 
literature for evidence to support the combination, and discuss the potential 
challenges and future directions for rational conduct of clinical trials.