Exposure to arsenic in contaminated drinking water is an emerging public health problem that impacts more than 200 million people worldwide. Accumulating lines of evidence from epidemiological studies revealed that chronic exposure to arsenic can result in various human diseases, including cancer, type 2 diabetes, and neurodegenerative disorders. Arsenic is also classified as a Group I human carcinogen. In this review, we survey extensively different modes of action for arsenic-induced carcinogenesis, with focus being placed on arsenic-mediated impairment of DNA repair pathways. Inorganic arsenic can be bioactivated by methylation, and the ensuing products are highly genotoxic. Bioactivation of arsenicals also elicits the production of reactive oxygen and nitrogen species (ROS & RNS), which can directly damage DNA and modify cysteine residues in proteins. Results from recent studies suggest zinc finger proteins as crucial molecular targets for direct binding to As and/or for modifications by arsenic-induced ROS/RNS, which may constitute a common mechanism underlying arsenic-induced perturbations of DNA repair.