Several researchers have explored the possibility that acute stimulant response may predict eventual improvement after specific antidepressants. This review analyzes the relationship between stimulant response and nonspecific antidepressant response. In five studies, amphetamine responders were found to eventually improve after antidepressant treatment in 85% of the cases, while nonresponders improved in 43% of the cases. In contrast, acute methylphenidate responders and nonresponders eventually improved on antidepressants at equivalent rates. Amphetamine sensitivity appears to be a trait (possibly pharmacodynamic) that is independent of depressive illness but predictive of tricyclic responsiveness. Other evidence has suggested that amphetamine and methylphenidate cause similar behavioral and symptomatic effects through distinct mechanisms of potential clinical relevance. The most effective method for administering an amphetamine challenge and its appropriate clinical use remain unclear.