Exposure to arsenic, a toxic metalloid distributed widely in nature, has been known to result in hazardous health outcomes including cancer. Incidence of arsenic toxicity, mostly from usage of underground water, has been reported from different corners of the world spanning more than 21 countries. Recent studies have radically influenced our knowledge on the level of toxicity imparted by different chemical forms of the metalloid. To understand the basic biology for arsenic metabolism different species have been studied at the molecular level, which has unraveled a wealth of information. However, there is no ideal animal model that can be used to understand arsenic toxicity in humans prompting the investigators to undertake the study directly in human cell lines and on affected individuals in areas of exposure. It is interesting to note that only a subset of exposed individuals demonstrate pathological features, i.e. skin lesions sometimes followed by cancer. Also, the extent of affectedness varies remarkably between individuals exposed to similar levels of arsenic. These observations led to investigation of genomic variation in exposed individuals as a potential contributing factor for differential susceptibility. An impressive number of studies have been published on variation in global gene expression and the potential association of candidate genes with arsenic-induced pathology. While there are excellent reviews relating to arsenic metabolism in general, there is no comprehensive review presenting the studies described in humans related to the metalloid toxicity. Our goal in this article has been to present the current state of research on this area to help formulate strategies for future studies.