Although melanomas are substantially more immunogenic than other tumors, current immunotherapeutic approaches for melanoma patients have met with only limited success. Although melanoma-specific CD8+ T-cell responses can often be generated in patients naturally or through vaccination regimens, tumors frequently continue to grow unabated, suggesting that tumor-specific immune responses may be actively dampened in vivo. Research over the past decade has brought to light several mechanisms used by melanomas and other tumors to suppress tumor-specific immune responses. These include the presence of regulatory immune cells within the tumor microenvironment and draining lymph nodes that serve to shut down effector T-cell function. In addition, melanoma tumors themselves express a number of soluble and membrane-bound molecules that are responsible for inhibiting activated immune cells. The identification of these suppressive mechanisms has provided significant opportunities for designing novel therapeutic interventions that could augment current vaccination and adoptive transfer approaches for treatment of melanoma.