Hexavalent chromium [Cr(VI)] compounds are known human carcinogens associated with the incidence of lung cancer. Although a direct co-relation between Cr(VI) exposure and lung cancer has been established, several studies aimed at generating animal models for Cr(VI) have yielded inconsistent data that does not support findings from epidemiological studies affirmatively. Since the lack of a good animal model has hindered the identification of molecular mechanisms involved in Cr(VI) exposure, we developed an in vitro model that facilitated mechanistic studies of Cr(VI)-induced carcinogenesis. We report here that long-term exposure to Cr(VI) leads to the malignant transformation of non-tumorigenic human lung epithelial cells. Cr(VI)-transformed cells exhibited loss of contact inhibition, colony formation, and increased rates of cell invasion, migration and proliferation as compared to passage-matched control cells. Cr(VI)-transformed cells evaded apoptosis by a mechanism involving S-nitrosylation and stabilization of Bcl-2 protein in a nitric oxide dependent manner. This study establishes an important in vitro model that facilitates mechanistic studies of Cr(VI)-induced carcinogenesis, and elucidates a novel mechanism that causes apoptosis-resistant malignant transformation of non-tumorigenic lung cells in response to a human carcinogen.