This commentary provides an overview of recent examples of pharmacometrics applied during the clinical development of two antagonists of the programmed death-1 (PD-1) cell surface receptor, pembrolizumab and nivolumab. Despite the remarkable achievements obtained in predicting the correct dosing schedule from different quantitative approaches, data indicated a great degree of heterogeneity in tumor response. To achieve therapeutic goals the search for predictive biomarkers associated with a lack of response and mechanism-based combination studies are warranted.