"Agonist therapy" for cocaine and methamphetamine addiction involves administration of stimulant-like medications (e.g., monoamine releasers) to reduce withdrawal symptoms and prevent relapse. A significant problem with this strategy is that many candidate medications possess abuse liability because of activation of mesolimbic dopamine (DA) neurons in the brain. One way to reduce DA-mediated abuse liability of candidate drugs is to add in serotonin (5-HT) releasing properties, since substantial evidence shows that 5-HT neurons provide an inhibitory influence over mesolimbic DA neurons. This article addresses several key issues related to the development of dual DA/5-HT releasers for the treatment of substance use disorders. First, the authors briefly summarize the evidence supporting a dual deficit in DA and 5-HT function during withdrawal from chronic cocaine or alcohol abuse. Second, the authors discuss data demonstrating that 5HT release can dampen DA-mediated stimulant effects, and the "antistimulant" role of 5-HT-sub(2C) receptors is considered. Next, the mechanisms underlying potential adverse effects of 5-HT releasers are described. Finally, the authors discuss recently published data with PAL-287, a novel nonamphetamine DA/5-HT releasing agent that suppresses cocaine self-administration but lacks positive reinforcing properties. It is concluded that DA/5-HT releasers could be useful therapeutic adjuncts for the treatment of cocaine and alcohol addictions, as well as for obesity, attention-deficit disorder, and depression.