Psychopharmacologic challenge procedures offer many useful features for biological psychiatry research. First, challenge procedures acutely stimulate neurotransmitter and (or) hormonal systems in the brain and offer the chance to assess the function, and (or) reserve, of the brain neurotransmitter/hormone system of relevance. Second, these paradigms often offer functional information about specific areas of the brain (e.g., limbic-hypothalamus). Regardless of these advantages, the power of these procedures is limited to the specificity of the agent and of the functional anatomy of the "circuit" that leads to the outcome measure, which, in turn, is linked to the stimulation by the acute pharmacologic challenge. We describe here the development of the psychopharmacologic challenge methodology and the strengths and weaknesses of this approach. Finally, the application of this paradigm in the study of various neuropsychiatric disorders will be reviewed and critiqued.