Most tumors are unresponsive to immune checkpoint blockade, especially if deep immunosuppression in the tumor develops prior to and prevents T cell immunosurveillance. Failed or frustrated T cell priming often needs repair before successful sensitization to PD-1/PD-L1 blockade. CD40 activation plays a critical role in generating T cell immunity, by activating dendritic cells, and converting cold tumors to hot. In preclinical studies, agonistic CD40 antibodies demonstrate T cell-dependent anti-tumor activity, especially in combination with chemotherapy, checkpoint inhibitory antibodies, and other immune modulators. With the advent of multiple CD40 agonists with acceptable single-agent toxicity, clinical evaluation of CD40 combinations has accelerated.