Recently, the Food and Drug Administration approved a new drug, varenicline, to help people quit smoking. It is the first new smoking cessation drug in nearly a decade, and joins just two other pharmacotherapy approaches [nicotine replacement therapies (NRTs) and bupropion] that have been proven effective for the treatment of tobacco dependence. However, even the most effective treatments help just one in four smokers quit longterm. Smoking is the single most preventable cause of death in the U.S., killing nearly 440,000 Americans each year. Nearly 45 million Americans smoke, and about 32 million of them would like to quit. Evolving knowledge about the human genome and the neurobiology of nicotine addiction holds great potential for improving smoking cessation treatments. This Issue Brief reviews ongoing work at Penn’s Transdisciplinary Tobacco Use Research Center (TTURC) to unravel the genetic factors that might affect smoking cessation and to develop more effective treatment strategies.