Skin cancer is the most common form of cancer in the U.S and is commonly driven by exposure to environmental factors. A major environmental risk factor for skin cancer development is through chronic arsenic exposure. Arsenic is a metalloid that is found naturally within the Earth’s crust. Arsenic can leach into neighboring bodies of water and lead to their contamination. As such, the major mechanism by which people are exposed to arsenic is through ingestion of contaminated drinking water. However, the mechanisms of that underlie arsenic tumorigenicity remain incompletely understood. With the threat of climate change, overirrigation, and unpredictable weather patterns, arsenic levels may continue to rise and pose a sizable public health risk. Increasing our understanding of the mechanisms that underlie arsenic tumorigenicity remains paramount. Here, I present my doctoral research, which unveils novel insights into arsenic-induced skin tumorigenicity, arsenic biochemistry, and RNA epitranscriptomics. Here, we establish that ALKBH1 is an oncogene that promotes arsenic-induced skin cancer. Using a model of in vitro arsenic-induced skin transformation, we find that ALKBH1 protein levels are up-regulated in arsenic-transformed keratinocytes, as compared to normal keratinocytes, and that ALKBH1 is up-regulated at early stages in the arsenic-induced transformation process. We identify that arsenic promotes ALKBH1 protein stability through complex mechanisms, including regulation by the proteasome and autophagy. Furthermore, we establish that knockdown of ALKBH1 in arsenic-transformed keratinocytes leads to decreased tumorigenicity, as evidenced by decreased cell proliferation, colony formation, growth in soft agar, and tumor growth in nude mice. Our findings establish that ALKBH1 is highly oncogenic and suggest that ALKBH1 may be a novel therapeutic target for the treatment of arsenic-induced skin cancer, as well as other ALKBH1-driven cancers. We also identify that arsenic can bind to the human ALKBH1 protein at cysteine residues. Our findings highlight that the binding between ALKBH1 and arsenic may be critical for ALKBH1’s oncogenic function and may also be required in regulating the substrate specificity of ALKBH1. Overall, our findings unveil a novel and complex interaction between arsenic and ALKBH1. Furthermore, we establish that ALKBH1, a demethylase with broad substrate specificity, may be induced to demethylate N6-methyladenosine (m6A) in mRNA in the presence of arsenic. We find that knockdown of ALKBH1 in arsenic-transformed keratinocytes leads to increases in m6A in mRNA and does not affect the expression of other m6A modifiers. Using a cell-free system, we identified that this apparent change in substrate specificity is directly due to arsenic, which we hypothesize promotes a re-wiring of the ALKBH1 protein functionality. Mechanistically, we also identify NR2C2 as an m6A-dependent target of ALKBH1 that functions as a tumor suppressor and a promotes changes in global mTOR-mediated translation.