Environmental and dietary carcinogens such as polycyclic aromatic hydrocarbons (PAHs) have been intensively studied for decades. Although the genotoxicity of these compounds is well characterized (i.e., formation of bulky PAH-DNA adducts), molecular details on the DNA damage response triggered by PAHs in cells and tissues remain to be clarified. The conversion of hazardous PAHs into carcinogenic intermediates depends on enzyme-catalyzed biotransformation. Certain cytochrome P450-dependent monooxygenases (CYPs) play a pivotal role in PAH metabolism. In particular, CYP1A1 and 1B1 catalyze oxidation of PAHs toward primary epoxide species that can further be converted into multiple follow-up products, both nonenzymatically and enzymatically. Distinct functions between these major CYP enzymes have only been appreciated since transgenic animal models had been derived. Electrophilic PAH metabolites are capable of forming stable DNA adducts or to promote depurination at damaged nucleotide sites. During the following DNA replication cycle, bulky PAH-DNA adducts may be converted into mutations, thereby affecting hot spot sites in regulatory important genes such as Ras, p53, and others. Depending on the degree of DNA distortion and cell cycle progression, PAH-DNA adducts trigger nucleotide excision repair (NER) and various DNA damage responses that might include TP53-dependent apoptosis in certain cell types. In fact, cellular responses to bulky PAH-DNA damage are complex because distinct signaling branches such as ATM/ATR, NER, TP53, but also MAP kinases, interact and cooperate to determine the overall outcome to cellular injuries initiated by PAH-DNA adducts. Further, PAHs and other xenobiotics can also confer DNA damage via an alternative route of metabolic activation, which leads to the generation of PAH semiquinone radicals and reactive oxygen species (ROS). One-electron oxidations mediated by peroxidases or other enzymes can result in PAH radical cations that mainly form unstable DNA adducts subjected to depurination. In addition, generation of ROS can also trigger multiple cellular signaling pathways not directly related to mutagenic or cytotoxic effects, including those mediated by NFκB, SAPK/JNK, and p38. In recent years, it became clear that PAHs may also be involved in inflammatory diseases, autoimmune disorders, or atherosclerosis. Further research is under way to better characterize the significance of such newly recognized systemic effects of PAHs and to reconsider risk assessment for human health.