The major conclusions of the 2010 Surgeon General’s report “How Tobacco Smoke Causes Disease” include “Through multiple defined mechanisms, the risk and severity of many adverse health outcomes caused by smoking are directly related to the duration and level of exposure to tobacco smoke.” The complexity of the toxicology of cigarette smoke is underscored by the list of 93 harmful or potentially harmful constituents (HPHCs) released by the Center for Tobacco Products. Individual constituents account for only a limited portion of the risk from smoking, and a large part of the risk cannot be accounted for by the total contribution of known harmful constituents. Harm reduction strategies that reduce exposure to tobacco smoke may have an advantage over reduction of individual smoke constituents or classes of constituents. One strategy is for smokers to switch to cigarettes that deliver a satisfactory level of nicotine while reducing exposure to other smoke constituents. Observations of studies using cigarettes with lower tar-to-nicotine ratios, generally produced by fortifying the cigarette filler with added nicotine, were reviewed by Russell in 2000 (In: Nicotine and Public Health, pp. 265-284, American Public Health Association). 22nd Century Group, Inc. has initiated studies of smokers switching to lower tar-to-nicotine ratio (LTN) cigarettes with higher nicotine content as a potential strategy to reduce smoke exposure. Cigarette consumption and biomarkers of exposure to selected smoke HPHCs of different chemical classes are measured. Values after switching to LTN cigarettes are compared to baseline, and to values for smokers continuing to smoke cigarettes with conventional nicotine content