The decline in approval of new drugs during the past decade has led to a close 
analysis of the drug discovery process. One of the main reasons for attrition is 
preclinical toxicity, frequently attributed to the generation of 
protein-reactive drug metabolites. In this review, we present a critique of such 
reactive metabolites and evaluate the evidence linking them to observed toxic 
effects. Methodology for the characterization of reactive metabolites has 
advanced greatly in recent years, and is summarized first. Next, we consider the 
inhibition of key metabolic enzymes by electrophilic metabolites, as well as 
unfavorable drug-drug interactions that may ensue. One important class of 
protein-reactive metabolites, not linked conclusively to a toxic event, is acyl 
glucuronides. Their properties are discussed in light of the safety 
characteristics of carboxylic acid containing drugs. Many adverse drug reactions 
(ADRs) are known collectively as idiosyncratic events, that is, not predictable 
from knowledge of the pharmacology and pharmacokinetics of the parent compound. 
Observed ADRs may take various forms. Specific organ injury, particularly of the 
liver, is the most direct: we examine this in some detail. Moving to the 
cellular level, we also consider the upregulation of induced cellular processes. 
The related, but distinct, issue of hypersensitivity or allergic reactions to 
drugs and their metabolites, possibly via the immune system, is considered next. 
Finally, we discuss the impact of such data on the drug discovery process, both 
through early detection of reactive metabolites and informed synthetic design, 
which eliminates unfavorable functionality from drug candidates.