Immunity-related GTPases (IRG) (also known as p47 GTPases) are a family of proteins found in vertebrates, which play critical roles in mediating innate resistance to intracellular pathogens. The proteins are expressed at high levels following infection with bacteria, protozoa or viruses, as a consequence of interferon-stimulated transcription. Their absence in gene-targeted mice leads to profoundly decreased resistance to many bacteria and protozoa that varies markedly with the particular IRG protein that has been targeted. The proteins are thought to function by localizing to pathogen-containing vacuoles in host cells, such as macrophages, and then regulating the processing of the vacuole and ultimately driving elimination of the pathogen. This review details current knowledge of IRG proteins and their key roles in host resistance.