Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer and a leading cause of cancer-related deaths worldwide, has prompted exploration into innovative treatment avenues. Notably, cancer immunotherapy has emerged as a promising strategy, with immune checkpoint inhibitors, specifically targeting the programmed cell death 1 (PD-1) and its ligand (PD-L1), revolutionizing cancer care. PD-1 is a crucial protein in suppressing immune responses and promoting self-tolerance by regulating T-cell function. The PD-1/PD-L1 axis is responsible for immune evasion in cancer cells making it a focal point in cancer therapy. However, despite the potential of PD-1/PD-L1 inhibitors, their clinical utility is hampered by significant immune-related adverse effects. This underscores the urgency to develop novel inhibitors, including small molecules and peptides that target the PD-1/PD-L1 axis to better meet clinical demands. This review focuses on elucidating the biological mechanisms of PD-1/PD-L1 immune checkpoints and their role in both the healthy immune system and the tumor microenvironment. Limitations to this treatment approach include low response rates in certain cancers, immune-related toxicity, and the development of drug resistance. Overcoming these limitations is crucial to expand the use of PD-1/PD-L1 blockade in cancer treatment and improve response rates and survival times for cancer patients