Abuse of illicit substances, in particular psychostimulants and opiates, is a worldwide public health issue. Chronic use of cocaine and amphetamine causes common neurobiological adaptations that may guide new treatment development. These include perturbations in dopamine and serotonin neurotransmission, leading to trials of antidepressants, and serotonin and dopamine augmentation strategies. The detection of cerebral perfusion abnormalities caused by psychostimulants has led to examination of antiplatelet and excitatory amino acid (EAA) antagonist therapies. Further, development of cocaine vaccines allows for testing of peripheral blockade approaches to cocaine addiction. New approaches to behavioral treatments for cocaine dependence are also reviewed. For opiate dependence, understanding of heroin's effects on mu and kappa opiate receptors has led to investigations of the partial mu agonist buprenorphine in opiate maintenance. Evidence for hyper-excitability of locus coeruleus (LC) noradrenergic neurons and EEA inputs to the LC guides trials of new alpha 2-adrenergic agonists and EEA antagonists to alleviate opiate withdrawal. Finally, clinical experience with withdrawal from methadone and LAAM has led to trials of antagonist-accelerated opiate withdrawal. Improved treatment of psychostimulant and opiate addiction is critically needed, and likely to have wide-reaching impact in health care and society.