Humans are exposed to arsenicals through many routes with the most common being drinking water. Exposure to arsenic has been associated with an increased incidence of skin, lung, liver, prostate, and bladder cancer. Although the relationship between arsenic exposure and carcinogenesis is well documented, the mechanisms by which arsenic participates in tumorigenesis are not fully elucidated. We evaluated the potential epigenetic component of arsenical action by assessing the histone acetylation and DNA methylation state of 13,000 human gene promoters in a cell line model of arsenical-mediated malignant transformation. We show changes in histone H3 acetylation and DNA methylation occur during arsenical-induced malignant transformation, each of which is linked to the expression state of the associated gene. These epigenetic changes occurred non-randomly and targeted common promoters whether the selection was performed with arsenite [As(III)] or with the As(III) metabolite monomethylarsonous acid [MMA(III)]. The epigenetic alterations of these promoters and associated malignant phenotypes were stable after the removal of the transforming arsenical. One of the affected regions was the promoter of WNT5A. This gene is transcriptionally activated during arsenical induced malignant transformation and its promoter region exhibited alterations in each of the four histone modifications examined which were linked to its transcriptional activation. Experimental reduction of WNT5A transcript levels resulted in abrogated anchorage independent growth, suggesting a participative role for the epigenetic remodeling of this promoter region in arsenical-induced malignant transformation. Taken together, these data suggest that arsenicals may participate in tumorigenesis by stably altering the DNA methylation and histone modifications associated with targeted genes, uncovering a likely set of participative genes and representing a mechanism to potentially explain the latency associated with arsenic-induced malignancy.