Improvements in in vitro ADME tools and pharmacokinetic prediction models have helped to shift attrition rates in early clinical trials from poor exposure to drug safety concerns, such as drug-induced liver injury (DILI). Assessing a new chemical entity's potential for liver toxicity is an important consideration for the likely success of new drug candidates. Reactive intermediates produced during drug metabolism have been implicated as a cause of DILI, and their formation has been correlated to the addition of a black box warning on a drug label. In this work, we will present contemporary examples of the bioactivation of atypical structures usually regarded as benign and often used by medicinal chemists when attempting to avoid bioactivation. Medicinal chemistry strategies used to derisk bioactivation will be discussed, and an emphasis will be placed on the necessity of a multidisciplinary approach.