Chronic antigen signaling drives CD8+T cell exhaustion (TEX) in cancer and chronic infection. However, how the kinase cascades downstream of the T cell receptor drive exhaustion is not understood. We found that continuous agonism of protein kinase C (PKC) causes degradation of PKC theta, but not PKC eta, and induces terminal TEXcells. During chronic infection, PKC theta is necessary to maintain the progenitor exhausted (TEX-PROG) cells, and thus the antigen-specific T cell response, while agonism of PKC eta promotes terminal exhaustion (TEX-TERM)in vitroandin vivo. The cascades downstream of these kinases are distinct, with PKC theta promoting activity of canonical PKC targets in the MAPK and CDK families, while eta promotes activity of other targets, including casein kinase I G2 (CK1G2). Expression of an engineered, degradation-resistant PKC theta, or deletion of the gene encoding CK1G2, improves T cell function and tumor control. Our illustration of multiple therapeutic avenues arising from targeting PKC highlights its centrality in TEXdifferentiation and its clinical potential in cancer immunotherapy.HighlightsPKC theta sustains T cell function while PKC eta promotes terminal exhaustionPKC theta and eta drive distinct phospho-cascades to oppose each other’s differentiation instructionsAn engineered, degradation-resistant PKC theta improves T cell responses in chronic infection and cancerAblation of kinase CK1G2 downstream of PKC eta improves anti-tumor T cell responses