The relevance of tobacco use to human health and longevity is obvious and indisputable. Despite reduced prevalence, cigarette smoking remains the largest cause of preventable mortality in the U.S. and worldwide. Promoting smoking cessation is a primary goal of tobacco control policies. Although three medications are currently prescribed to help people quit (varenicline, nicotine replacement therapy and bupropion), and more than half of American smokers attempt to quit annually, only 6% succeed. Therefore, a significant need for improved smoking cessation therapy remains, and has the potential to make a huge positive impact on longevity and individual quality of life. We have discovered that heritable differences in a human gene, FMO3, are correlated with the urge to smoke among smokers seeking to quit. We propose that this is caused by differences in the metabolism of nicotine in the brain. We will test this hypothesis in mice addicted to nicotine using mice with altered FMO genes or by feeding them a compound that inhibits FMO activity. If reducing FMO activity leads to reduced nicotine withdrawal symptoms in mice it may also work as a therapy to help smokers quit. Because smoking is such a large public health problem and quitting has near-immediate health benefits, even modest improvements in the current rate of quitting could mean longer life for millions of people.