Immune checkpoint inhibitors have dramatically transformed melanoma treatment options. However, intrinsic and acquired resistance remain fundamental limitations to extending the benefits to all patients. Understanding molecular and clinical features that correlate with response to treatment (biomarkers) may unravel therapeutic resistance, assist in treatment decision-making, and facilitate drug development. An intensive effort to characterize these biomarkers is underway. Herein, we highlight promising molecular biomarkers involving the tumor microenvironment, host immune response, and microbiome. We particularly focus on anti-programmed death-1 therapy but will also briefly cover anti-cytotoxic T lymphocyte antigen-4 and novel combination therapies.Over the past 5 to 10 years, a completely new class of immune therapies, termed immune checkpoint inhibitors, has been introduced. Monoclonal antibodies targeting programmed death-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) have now utterly changed the prognosis of patients with high risk and metastatic melanoma as well as other cancers.