A comprehensive analysis of published data indicates that arsenic exposure induces cardiovascular diseases, developmental abnormalities, neurologic and neurobehavioral disorders, diabetes, hearing loss, hematologic disorders, and various types of cancer. Although exposure may occur via the dermal, and parenteral routes, the main pathways of exposure include ingestion, and inhalation. The severity of adverse health effects is related to the chemical form of arsenic, and is also time- and dose-dependent. Recent reports have pointed out that arsenic poisoning appears to be one of the major public health problems of pandemic nature. Acute and chronic exposure to arsenic has been reported in several countries of the world where a large proportion of drinking water (groundwater) is contaminated with high concentrations of arsenic. Research has also pointed significantly higher standardized mortality rates for cancers of the bladder, kidney, skin, liver, and colon in many areas of arsenic pollution. There is therefore a great need for developing a comprehensive health risk assessment (RA) concept that should be used by public health officials and environmental managers for an effective management of the health effects associated with arsenic exposure. With a special emphasis on arsenic toxicity, mutagenesis, and carcinogenesis, this paper is aimed at using the National Academy of Science's RA framework as a guide, for developing a RA paradigm for arsenic based on a comprehensive analysis of the currently available scientific information on its physical and chemical properties, production and use, fate and transport, toxicokinetics, systemic and carcinogenic health effects, regulatory and health guidelines, analytical guidelines and treatment technologies.