Abstract: In 2011, the FDA approved ipilimumab, the first immune checkpoint inhibitor(ICI), targeting CTLA-4, opening the field of immune checkpoint therapy (ICT). ICIs can induce durable clinical responses and improve survival in selected population. However, significant challenges still remain, including mechanisms of resistance, patient selection, management of serious immune-related adverse events, and rational therapeutic combinations. This review surveys the current understanding of response and resistance to ICIs and proposes a path forward to improving efficacy and minimizing toxicities.