Drug-induced liver injury (DILI) is one of the major reasons for the termination of drug candidates in the development and the withdrawal of drugs from the market. Significant efforts are being made to utilize existing knowledge of chemical and biological mechanisms that have been linked with causing DILI. These mechanisms are often varied and can include overt chemical reactivity or bioactivation to reactive metabolites; unintended interactions with cellular proteins such as transporters and nuclear receptors; or the disruption of cellular processes like mitochondrial function and oxidative stress. For DILI to be observed the chemical needs (1) to possess the required chemical features to disrupt biological processes and (2) to reach a certain concentration in the liver. Structure–activity relationships (SARs) are often used to determine whether a chemical possesses the required features to disrupt a biological process. Whereas the concentration of a drug in the liver is highly dependent on its physicochemical properties as these influence many pharmacokinetic characteristics. However, despite the ability to assess compounds for their potential to cause DILI using in silico methods in combination with a battery of in vitro assays, it is often difficult to accurately predict the risk for a specific compound as the efficacious concentration is often not truly known until it reaches the clinic and is tested in man. In addition, the complexities of mechanisms that can lead to hepatotoxicity make the accurate identification of liver toxicants a challenging task. This chapter summarizes the importance of the consideration of physicochemical properties while applying SARs for toxicity assessment.