Programmed cell death protein 1 (PD-1) and its ligand PD-L1 play crucial roles in immune evasion by cancer cells, including in colorectal cancer (CRC). In immuno-oncology, targeting the PD-1/PD-L1 pathway has emerged as a promising therapeutic strategy for various cancers. PD-1 is an inhibitory receptor expressed on the surface of T cells, B cells, and natural killer (NK) cells. When PD-1 binds to its ligands, PD-L1 or PD-L2, it transmits an inhibitory signal that reduces T cell activity, leading to decreased proliferation, cytokine production, and cytotoxic activity. PD-L1 is often upregulated on the surface of cancer cells and TAMs within the TME. This upregulation helps tumors evade immune surveillance by inhibiting the activity of PD-1-expressing T cells. The PD-1/PD-L1 pathway plays a pivotal role in immune evasion by CRC, particularly in microsatellite instability-high (MSI-H)/ mismatch repair deficient (dMMR) tumors. US FDA approved PD-1 inhibitors such as pembrolizumab and nivolumab have shown significant efficacy in this subset of patients, leading to improved clinical outcomes. Combination therapies and emerging approaches are being actively investigated to extend the benefits of PD-1 blockade to a broader range of CRC patients, including those with microsatellite stable (MSS) tumors.