Both nicotine replacement and sustained-release buproprion double the odds of achieving short- and moderate-term abstinence from nicotine. However, questions remain about the efficacy of combining pharmacotherapies. Our purposes were to review the evidence for (1) combined pharmacotherapy and (2) multimodal treatment combining pharmacotherapy and behavioral treatment and to recommend combinations of treatments to reduce nicotine dependence. Combining first-line pharmacotherapies with each other or with investigational drugs shows little benefit. In contrast, trials combining specific behavioral treatments with first-line pharmacotherapies show enhanced smoking cessation rates, but benefits are not seen in all populations. We recommend future directions for research, including better specification of behavioral components and further examination of the length and timing of treatment.