PURPOSE OF REVIEW: Chronic inorganic arsenic (iAs) exposure affects over 220 million people throughout the world. Given that iAs is ubiquitous in the environment, it is important to understand the human health consequences of chronic iAs exposure. The purpose of this review is to highlight and evaluate research findings within the past 5 years that address the molecular mechanisms responsible for cancers caused by chronic iAs exposure. We also propose new research directions for the iAs research field based on the newest uncovered mechanisms for how this age-old poison promotes cancer. RECENT FINDINGS: Within the past 5 years, studies provide evidence that chronic iAs exposure promotes kidney, prostate, liver, and breast cancer in humans. New molecular mechanisms that promote cancer development by iAs exposure in skin, lung, bladder, kidney, prostate, liver, and breast include histone modifications, DNA and RNA methylation, non-coding RNA expression, disruption of alternative splicing, and inhibition of the DNA damage response. SUMMARY: Recent studies highlight disruption of epigenetic and epitranscriptomic modifications and/or the DNA damage response by chronic iAs exposure across many models of iAs-induced carcinogenesis, including cancers that are not classically defined as being caused by chronic iAs exposure. Understanding the molecular mechanisms underlying initiation and metastasis of iAs-induced cancers is essential for improving detection and targeted treatment of iAs-induced cancers.