The ability to avoid immune surveillance and destruction is one of the hallmarks of cancer. Identification of ligands that can prevent immune cells from killing malignant cells was the pivotal discovery for which the 2018 Nobel Prize in Medicine was awarded and initiated the current era in cancer immunotherapy. As a result, a number of antibody-based approaches including checkpoint inhibitors and bispecific antibodies have been explored. More recently, small molecule drugs have emerged as a complementary approach. Small molecules can offer unique advantages over antibody therapies including access to intracellular targets, opportunities for oral dosing, higher relative exposures in the brain, and increased penetration into tumors. This article provides a brief overview of antibody approaches and then summarizes nine immuno-oncology targets for which small molecule modulators have been described in the peer-review literature.