Considerable evidence exists that TSNA may cause cancer in humans. Strong evidence suggests that the NNN and NNK in snuff are at least partially responsible for the excess of oral cancer among snuff dippers. Tobacco smoke, because it is a combustion product, is a far more complex matrix than is smokeless tobacco. Nonetheless, NNK is well established as a lung carcinogen in laboratory animals at levels similar to those experienced by heavy smokers. Although the epidemiology of the smoking/lung cancer association has been studied extensively and is well established as a causal relationship, few attempts have been made to determine the effective constituents in tobacco smoke, much less to quantify them and to reduce their levels in consumer products. More work is needed to determine TSNA uptake in smokers and users of smokeless tobacco and to determine the factors involved in the possible endogenous formation of TSNA and in their metabolic activation or inhibition of their formation. Exploratory work is in progress with various biological markers that may prove useful in quantifying the levels of TSNA exposure in humans. Epidemiologic evidence indicates that in addition to tobacco use other factors are causally related to the development of cancers of the oral cavity, lung and esophagus and that these factors (e.g., radon exposure in uranium miners who smoke) can act synergistically. Experimental investigation of some of these synergistic effects may prove to be a step in the direction of determining the proportion of various cancers that are likely to be attributable to various causes and ultimately to the various constituents of tobacco exposure.