The development of immune checkpoint inhibitors (ICI) represents a major milestone in immune‐oncology. Over the years these agents have demonstrated efficacy in an increasing array of malignancies. Despite this success however, significant challenges remain. Novel approaches to both drug development and trial design are required to incorporate the unique pharmacokinetic and pharmacodynamic properties of ICIs. Further, it has also been established that the benefit of ICIs is limited to only a subset of patients. The molecular interactions between native immune cells and tumorigenesis and progression represent an active area of biomarker research, and elucidating the mechanisms of response and resistance is crucial to develop rational trial designs for the next wave of immune‐oncology (IO) clinical trials, particularly in patients with primary and/or acquired resistance. Efforts are now being made to integrate both biological and clinical information using novel multi‐omic approaches which are now being developed to further elucidate the molecular signatures associated with IO treatment response and resistance and enable rational drug development and trial design processes. As such, precision IO and the ability to deliver patient‐specific choices for ICI monotherapies or combination therapies has become an increasingly tangible goal. We herein describe the current landscape in ICI drug development and discuss the challenges and future directions in this exciting and evolving era in immune‐oncology.