Hypoxia is a condition in which bodily tissue is starved of oxygen. This lack of oxygen is common to many diseases, including cancer and stroke. Now, growing evidence suggests that hypoxia may activate immune cells, stimulating inflammation and possibly secondary injury. The role of programmed death-ligand 1, or PD-L1, in this process has attracted much attention recently. Normally, PD-L1 works like a “brake” on the immune system, keeping the immune response under control, but cancers can hotwire PD-L1 to make immune cells idle while tumor cells grow and multiply. Research shows that both persistent and intermittent hypoxia can trigger the overexpression of PD-L1 in various cells. These effects are closely related to the activity of HIF-1α, a protein critical to the body’s response to hypoxia. HIF-1α regulates PD-L1 expression by acting directly on the promoter region of the PD-L1 gene. As a result, PD‐L1 expression helps reduce autoimmune damage and maintain peripheral tolerance. Interestingly, PD-L1’s role in hypoxia varies between different diseases, including cancer, acute kidney injury, obstructive sleep apnea, and ischemic stroke. Understanding this versatility and further exploring PD-L1’s behavior is critical as it could lead to powerful new tools for diagnosing and treating hypoxia-related diseases.