The Hypoxia-Inducible Factor-1 (HIF-1) is a dimeric protein complex that plays a significant role in responding to low oxygen or hypoxia concentrations. Chronic inflammation is one of the immune system responses and can increase HIF expression in involved tissues through lowering the oxygen and hypoxia. The HIF factor has many critical roles in immunity, and thus, we reviewed the crucial roles of this factor in the immune system. The results showed various key roles on the immune system, including physical defenses, innate immune (neutrophils apoptosis, macrophages) and inflammatory responses (pyrexia and local heat, iron access, etc.), upregulation in response to microbial infections, cytokines expression (IL-1, IL-2, IL-6, IL-8, IL-12, IL-18, TNF, etc.), drug targeting, etc. The HIF roles in the acquired immune system include: enhance the adaptation of cells (dendritic cells) to new conditions and triggering the signal pathways. The findings of the present review demonstrated that the HIF has important roles in the immune system, including physical defense, innate immune as well as acquired immunity; therefore, it may be considered as a potent drug targeting several diseases such as cancers, infectious diseases, etc.