Polycyclic aromatic hydrocarbons (PAHs) are a class of over 1500 chemicals formed as incomplete combustion products and released into the environment from both natural (e.g. forest fires) or anthropogenic (e.g. burning of fossil fuels, tobacco, charbroiled meats) sources. Several PAHs, particularly those with more than 4 rings such as benzo[a]pyrene (BaP), dibenzo[def,p]chrysene (DBC), have been designated as Class 1 known or Class 2A probable human carcinogens by the International Agency for Research on Cancer (IARC, 2010). While much of the research on PAH carcinogenicity focuses on individual PAHs and BaP, in particular, most human exposures to PAHs result from chemical mixtures through dietary, inhalation, or dermal routes of exposure. Primary sources of environmental exposure to these PAHs include wood smoke, creosote, and burning of fossil fuels and tobacco (IARC, 2010). Recently, diesel engine exhaust was added to the list of Class 1 known human carcinogens and certain other PAH-containing mixtures, including air pollution, have been designated as probable or possible Class2A/B carcinogens in humans (IARC, 2010, 2014). One of the most difficult challenges for risk assessment is the evaluation of health hazards from exposure to environmental chemical mixtures. Currently, significant data gaps exist for understanding carcinogenicity of PAH mixtures and complex environmental mixtures containing PAHs. Further, little is known about the mechanisms of tumorigenesis for PAH mixtures. Current assessment of cancer risk for PAHs involves testing compounds in the 2-year rodent bioassay, which is not practical for screening large numbers of compounds or mixtures due to expense and time. Therefore, alternative approaches are typically utilized for evaluating the carcinogenic potential of PAHs and PAH-containing mixtures. Currently, the primary method for assessing cancer risk of complex mixtures is the relative potency factor (RPF) approach in which complex mixtures are evaluated based on a subset of individual component PAHs compared with BaP as a surrogate or reference (US EPA, 2010). However, we and others have found this approach inadequate for predicting carcinogenicity of mixtures and certain individual PAHs, particularly those that function through alternate pathways or exhibit greater promotional capacity compared to BaP (Courter et al., 2008; Siddens et al., 2012). Significant challenges have also been identified in utilizing such reference-based approaches for estimating risk from exposure to PAHs in air pollution or waste sites. Complex environmental mixtures subjected to weathering and aging processes can contain many different PAHs, including alkyl-, N-, S-, and O-substituted forms, along with other unknown chemicals; however, only a limited number of unsubstituted PAHs have been characterized for use in RPF calculations. Mixture toxicity for risk assessment is calculated based on select individual components and assumes additivity through a common mechanism of action for PAHs compared to BaP as a standard. Therefore, the RPF approach does not take into consideration mechanistic information about the different pathways, cells, and tissues affected by PAHs during initiation and promotion. This approach is also insufficient for predicting carcinogenicity of complex real-world environmental mixtures of unknown composition. In this study, we propose an innovative model for determining carcinogenic risk of PAH mixtures using mechanistic approaches. We hypothesize that a chemical bioactivity profile measured after short-term exposure to individual and mixture PAHs from global transcriptional profiling can be used to discriminate future carcinogenic potential based on important mechanistic differences among exposures. The bioactivity profile acts as a unique fingerprint for genes and pathways activated by chemicals and mixtures postexposure and can be used for predicting long-term consequences such as cancer outcome. An important aspect of the bioactivity profile is that the gene signatures are linked to chemical mechanism of action and can also provide insight into alternate mechanisms of PAH carcinogenesis and related mechanisms for complex mixtures. Based on preliminary data, we demonstrate that long-term cancer outcome for PAHs and mixtures can be predicted from high-content genomic evaluation of bioactivity after short-term exposure.