Inorganic arsenic (iAs), an environmental drinking water contaminant, is a human toxicant and carcinogen. The public health community has developed recommendations and regulations that limit human exposure to iAs in drinking water. Although there is a vast amount of information available to regulators on the exposure, disposition and the health-related effects of iAs, there is still critical information about the toxicology of this metalloid that is needed. This necessary information includes identification of the chemical species of arsenic that is (are) the active toxicant(s), the mode(s) of action for its various toxicities and information on potentially susceptible populations. Because of these unknown factors, the risk assessment of iAs still incorporates default assumptions, leading to uncertainties in the overall assessment. The characteristics of a scientifically defensible risk assessment for iAs are that it must: (1) quantitatively link exposure and target tissue dose of active metabolites to key events in the mode of action for major health effects and (2) identify sources of variation in susceptibility to arsenic-induced health effects and quantitatively evaluate their impact wherever possible. Integration of research to address these goals will better protect the health of iAs-exposed populations.