Retrospective studies indicate that many drugs that cause clinical adverse reactions, such as hepatotoxicity, undergo metabolic bioactivation, resulting in the formation of electrophilic intermediates capable of covalently modifying biological macromolecules. A logical extension of these findings is a working hypothesis that compounds with reduced levels of bioactivation should be inherently safer drug molecules and thus have a greater likelihood of success in drug development. Whereas some research-based pharmaceutical companies have adopted a strategy of addressing metabolic bioactivation early in drug discovery, much skepticism remains on whether such an approach would enable the industry to reach the desired objectives. The debate is centered on the question of whether there is a quantitative correlation between bioactivation and the severity of drug-treatment-related toxicity, and whether covalent protein modification represents only one of several possible mechanisms underlying observed tissue injury. This communication is intended to briefly review the current understanding of drug-induced hepatotoxicity and to discuss the controversy and future directions with respect to the effort of minimizing the probability of clinical adverse reactions.