Various forms of nicotine replacement therapy and bupropion have been found to be efficacious and well tolerated for treating patients dependent on tobacco. However, the currently recommended duration of treatment with pharmacotherapy may be insufficient for some smokers to achieve sustained abstinence from tobacco. Extending the use of pharmacotherapy beyond the recommended timeframe may be an effective strategy for helping tobacco users achieve abstinence and for preventing relapse to tobacco use, especially among those who are highly dependent and those who are concerned about bodyweight gain following cessation. Several studies have reported on long-term use of various pharmacotherapies. These studies have demonstrated that such long-term use is not harmful. Moreover, compared with continued smoking, long-term use of pharmacotherapy exposes patients to relatively small amounts of nicotine and none of the cancer-causing chemicals found in cigarettes and other tobacco products. However, more research is needed to further clarify questions regarding the ideal duration of therapy. Two questions have yet to be answered: In what populations of smokers is long-term therapy an effective strategy for achieving abstinence and preventing relapse? Does wider availability of nicotine replacement therapy lead to initiation of nicotine addiction by children and others not using tobacco products? Also, as with all medications, additional documentation of the safety of prolonged use of pharmacotherapy is important. The aim of this review is to present the current evidence supporting the notion that long-term therapy for treating tobacco dependence may be appropriately considered for some tobacco users.