Antibodies that block the PD-1 coinhibitory receptor on T cells or its primary ligand, PD-L1, have demonstrated unprecedented efficacy across a diverse array of both solid and hematologic malignancies in the clinic. These advances were built on a foundation of murine preclinical tumor model studies, which both demonstrated the therapeutic potential of PD-1/PD-L1 antibody blockade and also provided critical insights into the cellular and molecular processes underlying their capacity to elicit immune-mediated tumor regressions. As the field of immunotherapy moves toward higher-order combinations of agents, effective utilization of murine tumor models to optimize the composition of PD-1 antibody combination therapies, as well as their dosing and scheduling, will be essential for effective clinical translation. Novel murine models bearing human tumor xenografts and engrafted human immune systems may help close the gap between preclinical and clinical immunobiology.