Humans are exposed to heavy metals through a variety of occupational and non-occupational means. Growing evidence has accumulated that prolonged exposure to these heavy metals is associated with cancer occurrence at various body sites including lung, liver, bladder, colon, and skin. Much research effort has been placed on discovering the mechanisms by which heavy metals induce different kinds of cancers. Results from these mechanistic studies have varied for different metals, but increased activation of signaling pathways is often observed. This review will focus on the signaling molecules including epidermal growth factor receptor (EGFR), phosphatidyl inositol 3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR) in carcinogenesis and cancer progression; and how these molecules are affected by the exposure to heavy metals: arsenic, chromium, nickel, and cadmium. Furthermore, drug targets for the prevention and therapy of cancers induced by heavy metals will be discussed with a focus on drugs that are currently in clinical trials for these targets.