Hypoxia-inducible factor (HIF) is a transcriptional activator that coordinates adaptive responses to hypoxia. An increased activity is recognized in the majority of clinical relevant hypoxic/ischemic episodes and human cancers. However, studies with HIF-1alpha knockout mice revealed an important role of HIF-1 for physiology such as embryogenesis or glycolytic energy production. The discovery that HIF-1 activity is not only restricted to pathological conditions of reduced oxygen availability but also is needed for the normal O2-homeostasis by regulating O2-delivery and consumption opens a diverse spectrum of so far unappreciated HIF-1 functions in several organs, including the immune system. Innate immune responses are orchestrated by macrophages. These cells respond to environmental input signals and in turn generate appropriate answers to initiate resolution of inflammation. It appears that multiple pathways in the inflammatory microenvironment are used to adjust HIF-1alpha levels to affect macrophage biology. This review summarizes mechanisms of HIF activation in mammalian immune cells, especially in macrophages and neutrophils, and outlines how HIF moderates inflammation.