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The treatment of locally advanced rectal cancer (LARC) has seen major advances over the past 3 decades, with multimodality treatment now standard of care. Combining surgical resection with radiotherapy and/or chemotherapy can reduce local recurrence from around 20% to approximately 5%. Despite improvements in local control, distant recurrence and subsequent survival rates have not changed. Immune checkpoint inhibitors have improved patient outcomes in several solid tumor types in the neoadjuvant, adjuvant, and advanced disease setting; however, in colorectal cancer, most clinical trials have been performed in the metastatic setting and the benefits confined to microsatellite instability–high tumors. In this article, we review the current preclinical and clinical evidence for using immune checkpoint inhibition in the treatment of LARC and discuss the rationale for specifically exploring the use of this therapy in the neoadjuvant setting. We summarize and discuss relevant clinical trials that are currently in setup and recruiting to test this treatment strategy and reflect on unanswered questions that still need to be addressed within future research efforts.