Tobacco use is the single most important preventable cause of cancer-related deaths in the USA and many parts of the world. There is growing evidence that menthol cigarettes are starter tobacco products for children, adolescents, and young adults. Accumulating research also suggests that smoking menthol cigarettes reinforces nicotine dependence, impedes cessation, and promotes relapse. However, menthol cigarettes are exempt from the US Food and Drug Administration ban on flavored cigarettes due, in part, to the lack of empirical evidence describing the health consequences of smoking menthol cigarettes relative to regular cigarettes. Determining the biological effects of menthol cigarette smoke relative to regular cigarette smoke can clarify the health risks associated with the use of respective products and assist regulatory agencies in making scientifically based decisions on the development and evaluation of regulations on tobacco products to protect public health and to reduce tobacco use by minors. We highlight the inherent shortcomings of the conventional epidemiologic, clinical, and laboratory research on menthol cigarettes that have contributed to the ongoing debate on the public health impact of menthol in cigarettes. In addition, we provide perspectives on how future investigations exploiting state-of-the-art biomarkers of exposure and disease states can help answer the lingering question of menthol in cigarettes.With the enactment of the Family Smoking Prevention and Tobacco Control Act (FSPTCA) in 2009, the US Food and Drug Administration (FDA) was granted authority to regulate the manufacture, marketing, and distribution of tobacco products to protect public health and to reduce tobacco use by minors [1]. In 2011, the Tobacco Products Scientific Advisory Committee (TPSAC) reported to the FDA that ''menthol cigarettes damage public health,'' and recommended that ''removal of menthol cigarettes would benefit public health in the USA'' [2]. The TPSAC report has been substantiated by ample research, suggesting that smoking menthol cigarettes is a ''gateway'' to using other tobacco products, especially during childhood and early adulthood, increases nicotine addiction, deters quitting, and promotes relapse [3,4]. Because smoking is our nation's leading cause of preventable death [5,6], any ingredient that may encourage people to take up this deadly habit or reinforce this lethal addiction should be considered a significant public health concern. However, the FDA has not yet taken regulatory steps, including imposing a ban on menthol cigarettes despite banning all the other flavored cigarettes from the US market [1]. This lack of action may, in part, be due to the absence of empirical evidence describing the health consequences of smoking menthol cigarettes relative to regular cigarettes [7,8]. Finding scientific underpinnings for the adverse health effects of smoking menthol cigarettes relative to regular cigarettes is of significance because it can help advance the FDA's mission of developing an...