Globally, tobacco kills almost 5 million people around the world annually. Seven first-line pharmacotherapies are currently available and recommended by the United States Public Health Service (USPHS) clinical practice guideline for treating tobacco dependence, all of which have been proven to be effective for increasing tobacco abstinence rates when used as monotherapy. However, not all smokers are able to quit with single-drug therapy. Some smokers may benefit from combination therapy that includes the simultaneous use of different nicotine replacement therapies (NRTs) or medications with different mechanisms of action (e.g. NRT and bupropion). Combination therapy with different types of NRT may provide a therapeutic advantage by increasing serum nicotine concentrations, and combination therapy with different drugs may capitalize on synergy obtained from two different mechanisms of action. However, controversy exists regarding this approach. Available data suggests that combination therapy may increase abstinence rates compared with monotherapy. However, the cost effectiveness of this approach has not been clearly demonstrated.