A non-linear approach, consistent with available mode of action (MOA) data, is most scientifically defensible for assessing the carcinogenicity of oral exposure to hexavalent chromium (CrVI). Accordingly, the current paper builds upon previous studies (Haney, 2015a, 2015b) to first develop a non-linear, non-threshold approach as well as a non-linear threshold approach for assessing the oral carcinogenicity of CrVI, and then utilizes available MOA analyses and information for selection of the most scientifically-supported approach. More specifically, a non-linear, non-threshold dose–response function was developed that adequately describes the non-linearity predicted for potential human excess risk versus oral dose due to the sub-linear relationship between oral dose and internal dose (added mg Cr/kg target tissue) across environmentally-relevant doses of regulatory interest. Additionally, benchmark dose modeling was used to derive a reference dose (RfD of 0.003 mg/kg-day) with cytotoxicity-induced regenerative hyperplasia as a key precursor event to carcinogenesis in the mouse small intestine. This RfD value shows remarkable agreement with that published previously (0.006 mg/kg-day) based on a more scientifically-sophisticated, physiologically-based pharmacokinetic modeling approach (Thompson et al., 2013b). The RfD approach is the most scientifically-defensible approach based on the weight-of-evidence of available MOA information and analyses conducted for the most scientifically-supported MOA.