A scientific, evidence-based risk assessment method to assess potential health risks of individual tobacco smoke toxicants, reflecting the range of yields and human characteristics related to exposure, is a beneficial tool for tobacco product regulation and the establishment of product standards.In recent years there has been significant interest in characterising these individual toxicants both from the perspective of future regulatory frameworks aimed at monitoring or lowering toxicant levels and from the perspective of tobacco product development focused on selective toxicant reduction, using several different techniques (Fowles and Dybing 2003; Pankow et al. 2007; Burns et al. 2008; Watanabe et al. 2009; Talhout et al. 2011; Cunningham et al. 2011, Xie et al. 2012). A similar approach for smokeless tobacco products toxicants has also been presented (Ayo-Yusuf and Connolly 2011). A basic criticism of all the techniques employed to date is that they have been applied to individual toxicants rather than toxicants within the complex mixture of tobacco smoke. Progress has been made in the field of risk assessment of simple mixtures of chemicals but a complex mixture such as tobacco smoke presents additional challenges. We have initiated work to investigate the utility of the Margin of Exposure (MOE) segregation tool for use in small scale mixture assessment of three aldehydes (Cunningham et al. 2012) through careful consideration of their mode of action. We suggest that a data-driven, physiologically relevant risk assessment strategy is a useful tool for the identification and prioritization of tobacco smoke toxicants for risk reduction research prior to construction of a more complex mixture-based risk assessment platform.