Cigarette smoking continues to make an important impact on the health status and costs of care in the US. Animal studies demonstrated that ondansetron is effective in decreasing withdrawal behaviour and have led to interest in its role in smoking cessation. One small trial tested the effects of ondansetron as an aid to change smoking behaviors. The results did not support a beneficial effect of ondansetron use. There were several limitations of this study, including small sample size and potentially inadequate duration of therapy and follow-up. An oral ondansetron formulation recently has become available. There are several disadvantages to an oral versus an intravenous formulation of ondansetron. Patients taking oral therapy are at less risk, the administration of an oral preparation does not require trained personnel, and a study can be performed in an environment in which the influences of daily living can affect smoking behavior (e.g., early morning, and after a meal). Ultimately, well-defined, large-scale clinical studies are necessary to determine whether ondansetron has a positive effect on smoking cessation.