Despite the ability of immune-based interventions to dramatically increase the survival of patients with melanoma, a significant subset fail to benefit from this treatment, underscoring the need for accurate means to identify the patient population likely to respond to immunotherapy. Understanding how melanoma evades natural or manipulated immune responses could provide the information needed to identify such resistant individuals. Efforts to address this challenge are hampered by the vast immune diversity characterizing tumor microenvironments that remain largely understudied. It is thus important to more clearly elucidate the complex interactions that take place between the tumor microenvironment and host immune system.