Advances in the oncological sciences have led to the development of agents that are designed to affect specific molecular pathways. However, many of these immunotherapeutic agents do not successfully pass phase 2 trials due to concerns with efficacy, toxicity or side effects. The generalized endpoints that traditionally have been used in these trials, such as maximum tolerated dose and overall response, may be less optimal for immunotherapeutic agents. The addition of in vivo nuclear imaging in these early trials can aid in patient stratification, evaluation of drug bio distribution, pharmacodynamic effects and tumor heterogeneity. This review discusses the advantages of nuclear imaging, and outlines the first application of these imaging biomarkers in clinical trials.