This chapter discusses the multiple effects and mechanisms of arsenic on stem cells (SCs) and the resultant or potential disease manifestations or cures. It focuses on those studies that directly look at SCs in their work. SCs play a central role in an organism during all stages of growth and development and particularly in tissue repair response to toxic insult. Accumulating evidence indicates that SCs may be the target cell phenotype during arsenic‐induced carcinogenesis. Arsenic exposure alters SC dynamics, blocking the exit of SCs into differentiation, and induces an overabundance of cancer stem cells (CSCs) in various in vivo and in vitro model systems. Just as arsenic can act as a carcinogen, some forms, mainly arsenic trioxide (ATO), have been used as an effective chemotherapeutic, especially for various hematological malignancies. The studies discussed in the chapter provide strong evidence that SCs play a key role in this arsenic‐based disease outcome.