This paper describes the rationale and procedures for conducting what is considered by many to be the current "gold standard" for initial abuse liability testing of a novel compound: the classic acute dose-effect comparison study in volunteers with histories of drug abuse. Such a trial is most appropriate for predicting the likelihood of abuse by drug abusers and, in turn, the extent of drug diversion and illicit street sales if the novel compound became available in the community. The dose-effect abuse liability trial typically involves a double-blind complete crossover design in 10-14 subjects with histories of polydrug abuse in a controlled clinical pharmacology laboratory setting. Drug conditions usually involve placebo, three doses of the novel compound and three doses of an appropriate reference compound of known abuse liability. In each session, the time-course of effects of a single drug dose are evaluated. Intervals between experimental sessions are typically 1 to several days. The importance of testing high supra-therapeutic doses of the novel drug for the validity of the trial is emphasized, and the use of a dose run-up pilot study for selecting maximal doses and matching doses between the novel and comparison compound is explained. The rationale and description of outcome measures is discussed, including measures that reflect likelihood of abuse (e.g. drug vs. money choice and subject ratings of liking, good effects, estimated monetary street value), secondary measures that should be considered in interpreting likelihood of abuse (e.g. drug identification, subject-rated side effects and mood changes), and additional concurrent measures to establish equivalence of the novel and comparison compound (e.g. behavioral performance, observer-rated assessments, physiological measures).