The hypoxia-inducible transcription factor (HIF-1alpha) is a major regulator of energy homeostasis and cellular adaptation to low oxygen stress. Recently, HIF-1alpha has been discovered to function as a global regulator of macrophage and neutrophil inflammatory and innate immune functions, as befits these specialized phagocytic cells who must operate effectively in the hypoxic microenvironments of infected tissues. This review summarizes current knowledge of the role of HIF-1alpha in mammalian innate immunity, emphasizing insight gained from conditional gene targeting of the transcription factor in the myeloid cell lineage. Dynamic changes in HIF-1alpha expression in the course of bacterial, viral, or parasitic infections are outlined and inferences drawn regarding the consequences for pathogen and host. A better understanding of HIF-1alpha function may provide novel and rational approaches for boosting innate immune function in the therapy of certain complicated infectious disease conditions.