Chronic arsenic exposure increases risks for mortality and morbidity in humans. In addition to dose, duration of exposure and other host factors, the risks vary based on genetic status of individuals. We undertook some of the largest and most comprehensive genome-wide investigations of genetic susceptibility to metabolism and health effects of arsenic. Two major genetic loci have been identified to play significant roles: arsenic methyl-transferase gene on chromosome 10 and formiminotransferase cyclodeaminase gene on chromosome 21. Candidate gene studies found genes in the oxidative stress, DNA repair and immune pathways also to play roles. Our genome-wide investigations of gene expression and epigenetic variations identified novel genomic alterations induced by arsenic exposure in human. The presentation at the conference will integrate these findings, both published and unpublished, along with other recent key genomic investigations of arsenic metabolism and toxicity in different populations in the world.