The anti-programmed cell death-1 (PD-1) monoclonal antibodies pembrolizumab and nivolumab have been contingently approved for the treatment of patients with advanced melanoma based on their durable response, high response rate, and favorable safety profile. Mature survival data from randomized phase III trials are eagerly awaited to confirm their position as the standard-of-care frontline or second-line therapy in advanced melanoma management algorithm. The immune-related adverse events associated with these novel agents are somewhat different than those of ipilimumab, considering the manifestation of pneumonitis and acute renal failure. Active research is ongoing to identify biomarkers predictive of clinical benefit to the anti-PD1 monoclonal antibodies, to expand their utility in other disease settings, and to explore their safety and efficacy in combination with other therapeutic agents. Unanswered questions concerning optimal dosing schedule, treatment duration, and therapy sequencing will also need to be addressed in future investigations.