The study of a new drug includes the assessment of its pharmacologic effects, benefits (efficacy), and risks (safety). Most recent drug discontinuations in the United States and the United Kingdom have been associated with problems of safety. The assessment of clinical drug safety is difficult. Those assessing drug safety are confronted with the need to make causality assessment judgments of drug-related events. Several procedures for assessing causality of adverse reactions have been proposed; however, none of them is completely satisfactory. Global introspection (the unaided judgment based on knowledge and experience) and the currently available standardized decision aids (questionnaires or algorithms) have serious limitations that hamper their use. There is a need for better procedures.