Despite the broad clinical antitumor activity of PD-1/PD-L1 antagonists, many patients who are treated with these agents either do not respond or achieve suboptimal responses. Improving overall outcome will require combinations with other agents to address potential innate or acquired mechanisms of resistance. Many combination trials have been initiated in patients with or without prior exposure to the PD-1/PD-L1 antagonists. In addition to the challenge of identifying optimal dose, schedule, and sequence for the combinations, current biomarker efforts lack the precision to identify optimal combination partners for the PD-1/PD-L1 antagonists in individual patients. For each possible combination, careful consideration of clinical trial design, biomarker strategies, and endpoints for early clinical development will be necessary to move the most promising regimens forward and therefore to accelerate the rate of clinical progress.