Inhalation of hexavalent chromium [Cr(VI)] has been associated with increased lung cancer risk among workers of certain industries, but no well recognized or published mode of action (MOA) exists. Although it has been suggested that Cr(VI) acts by a mutagenic MOA because it damages DNA in vitro and in some in vivo tests, several recent reviews have concluded that Cr(VI) is only weakly mutagenic and that genetic/epigenetic changes resulting in genomic and/or microsatellite instability, inflammation, oxidative stress and deregulation of repair mechanisms play a role in carcinogenicity. Further, recent data for mouse small intestinal cancers caused by Cr(VI) in drinking water support a cytotoxic MOA involving chronic intestinal wound and healing. Using the modified Hill Criteria, we have reviewed kinetic, human, animal, and mechanistic data to develop a lung cancer MOA; evaluated plausibility, dose-response, and temporal concordance; and considered alternative MOAs. Among workers with an observed increase in lung cancer, respiratory tissue irritation and inflammation were common clinical findings, and in animal studies irritation and inflammation precede tumor formation in dose (≥50 μg/m3) and time (within 30 days), suggesting that cytotoxicity and inflammation are early key events. The overall evidence supports that Cr(VI) induces lung cancer by a non-mutagenic MOA involving oxidative stress, cytotoxicity, and inflammation, causing oxidative DNA damage, epigenetic DNA modifications and genomic instability, occurring at the high exposure concentrations. Further, extracellular Cr(VI) reduction in the lung limits absorption and may introduce non-linearity in the extrapolation of tissue dose from high to low exposures. Based on these findings, the risk assessment for inhalation exposure to Cr(VI) should consider intensity-based dose metrics and non-linear low dose extrapolation approaches.