While PD-1/PD-L1 blockade is a successful therapeutic approach for select patients with triple-negative breast cancer, identifying novel immunotherapeutics to broaden the potential application of immunotherapy remains an unmet need in breast cancer. In this chapter, the mechanism of action, preclinical data, and clinical data with safety and/or efficacy are reviewed for a number of targets, including adenosine, IDO1, LAG3, OX40, and TIM3. While single-agent activity may be observed with modulating these targets, combinatorial approaches with checkpoint inhibitors may lead to higher and more durable responses than those reported with single-agent PD-1/PD-L1 blockade. Currently, only checkpoint inhibitors are approved in the treatment of breast cancer. The targets described in this section may represent the next generation of treatment options for patients that may harness the immune system for therapeutic benefit.