Intravenous self-administration (IVSA) studies have shown that nicotine can serve as a reinforcer in -animals and humans. Brain mechanisms underlying nicotine IVSA, as well as the effects of pharmacological interventions, have also been widely investigated and are summarized. However, the conditions under which nicotine self-administration has been observed do not closely model the way in which nicotine is consumed by cigarette smokers, in two important respects: conventional IVSA procedures typically employ ultra-rapid infusions and high unit doses of nicotine that approximate the content of one or two cigarettes. In contrast, recent evidence shows that rats will also self-administer nicotine in doses equivalent to about two cigarette puffs, delivered into the circulation at a much slower rate that more closely approximates the delivery rate in cigarette smokers. Possibly, adoption of these refinements will help to provide an animal model with greater predictive clinical validity in order to advance the search for more effective smoking cessation pharmacotherapies. © 2011 Springer Science+Business Media, LLC.