U.S. regulations that set standards for acceptable concentrations of respirable particulate matter (PM) in outdoor air, particularly total fine particulate matter (PM(2.5)), are based largely on the belief that current concentrations cause death and illness, and that reducing these concentrations will save lives. Because the mortality risk estimates from important observational epidemiologic studies are extremely weak, derived from studies unable to control for relevant confounding causes, and inconsistent by location, toxicologic and clinical information is necessary to judge the likelihood and degree to which such findings are causal. Toxicologic data on typical forms of pollution-derived PM strongly suggest that current ambient concentrations in the U.S. are too small to cause significant disease or death. We review here the results of inhalation studies using concentrated ambient particles, diesel engine exhaust particulate matter, and sulfate and nitrate salts, and find no evidence that moderate concentrations are lethal. The expectation that lives will be saved by reducing ambient PM(2.5) in the U.S. is not supported by the weight of scientific evidence, although other bases for regulating PM may be justifiable.