Drug abuse is currently a large economic and societal burden in countries around the globe. Many drugs of abuse currently lack adequate therapies aimed at treating both the addiction and negative complications often associated with their use. Sigma-1 receptors were discovered over 30 years ago and have recently become targets for the development of pharmacotherapies aimed at treating substance abuse and addiction. In vivo preclinical studies have revealed that sigma receptor ligands are able to ameliorate select behavioral effects of many drugs of abuse including cocaine, methamphetamine, ethanol and nicotine. In addition, recent studies have begun to elucidate the mechanisms by which sigma-1 receptors modulate the effects of these drugs on neurotransmission, gene regulation and neuroplasticity. Overall, these recent findings suggest that compounds targeting sigma-1 receptors may represent a potential new class of therapeutics aimed at treating drug abuse. Future studies involving clinical populations will be critical for validating the therapeutic potential of sigma-1 receptor ligands for the treatment of substance abuse.