The use of '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 due to activation of mesolimbic dopamine (DA) neurons in the brain. One way to reduce DA-mediated abuse liability of candidate drugs might be 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 chapter addresses several key issues related to the development of dual DA/5-HT releasers for the treatment of substance use disorders. First, we briefly summarize the evidence supporting a dual deficit in DA and 5-HT function during withdrawal from chronic cocaine or alcohol abuse. Second, we discuss data demonstrating that 5-HT release can dampen DA-mediated stimulant effects, and the 'anti-stimulant' role of 5-HT(2C) receptors is considered. Next, the mechanisms underlying potential adverse effects of 5-HT releasers are described. Finally, we discuss recently published data with PAL-287, a novel non-amphetamine 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.