Passed in 2009, the Family Smoking Prevention and Tobacco Control Act granted the U.S. Food and Drug Administration (FDA) the authority to regulate tobacco products. Among the powers given the FDA in this landmark legislation was the authority to define what acceptable levels of certain chemical constituents may be, including compounds known to be toxicants. This agency was also given the charge to investigate the effects of altering nicotine yield on the addictiveness of tobacco products, and they have the power to mandate decreased levels of nicotine if deemed in the interest of overall human health. Molecular biology-based strategies have proven to be powerful tools in the efforts to reduce the levels of select toxicants in tobacco, as well as a means for modulating the levels of nicotine. In the great majority of these reports, however, the end product is a genetically modified (GM) plant, and to date all major international tobacco companies refuse to use GM tobacco in their products. Despite this obstacle, molecular technologies still have the potential to play a significant role in efforts to modify the chemical constituents of tobacco in a manner that may help the industry comply with what may become future “harm reduction”-related mandates. In addition to reviewing current progress in this area, the topic of emerging precision genome editing technologies will be reviewed, as these approaches provide new avenues of introducing desirable traits into the tobacco plant that are likely to be more acceptable to the industry and consumers than traditional GM technologies.