AbstractImmune checkpoint therapy (ICT) can provide durable clinical responses and improve overall survival. However, only subsets of patients with specific tumor types respond to ICT. Thus, significant challenges remain, including understanding pathways of resistance, optimizing patient selection, improving management of immune-related adverse events, and identifying rational therapeutic combinations. These challenges will need a focused approach encompassing both clinical and basic research, with the integration of reverse translational studies. This integrated approach will lead to identification of potential targets for subsequent clinical trials, which will guide decisions as we develop novel combination strategies to maximize efficacy and minimize toxicities for patients.Significance:ICTs induce durable antitumor responses for subsets of patients with cancer. Recent evidence suggests that rational combinatorial strategies can improve response by overcoming primary and adaptive resistance mechanisms, although these may carry an increased risk of immune-mediated toxicities. This review surveys the current understanding of mechanisms of response and resistance to ICTs and active areas of investigation, and proposes a path forward to improving efficacy and minimizing toxicities through better patient selection and rational combinations.