Perforin-2 (MPEG1) is a recently described pore-forming protein that facilitates the destruction of phagocytosed microbes. Gene ablation and siRNA studies have shown that Perforin-2 deficient macrophages and other phagocytes are inefficient killers of intracellular bacteria (4). Mice lacking Mpeg1 develop normally and thrive when raised under specific pathogen-free conditions. However, when challenged with bacterial pathogens they succumb to infectious doses that most of their wild-type littermates survive (2,3). For example, Citrobacter rodentium –a murine enteric pathogen– is largely confined to the gut and eventually cleared by immunocompetent mice. However, in one of our studies C. rodentium killed all Mpeg1 -/- mice within 11 days of orogastric inoculation. This was accompanied by dissemination of the pathogen to other internal organs and tissues. Heterozygous mice were found to have a gene dosage effect. Likewise, Mpeg1 haploinsufficiency in humans also appears to be associated with chronic and/or recurrent bacterial infections. For example, we recently concluded a case study with a team of physician scientists from UCLA who had been seeking the cause of a young patient’s susceptibility to an array of soft tissue bacterial infections (1). Genome sequencing revealed one of her Mpeg1 alleles carries a nonsense mutation; Y430*. Consistent with our murine and cell based studies we found that the patient’s neutrophils and macrophages are inefficient killers of phagocytosed bacteria. To date there are no known individuals with two defective alleles of Mpeg1. Based on our murine studies we suspect that such an individual would not survive to reproductive age. These and others studies have established that Perforin-2 underpins a pivotal function of macrophages and other phagocytes; the destruction of intracellular bacteria.