Eric Boyland and collaborator demonstrated about 20 years ago that N'-nitrosonornicotine (NNN), a suspected smoke constituent, was a lung carcinogen in mice and that thiocyanate, a major detoxification product of the smoke component hydrogen cyanide, catalyzes the endogenous formation of nitrosamines. Also, Boyland presumed that the enzymatic conversion of nicotine may contribute to the carcinogenic potential of cigarette smoke via reactive intermediates. Chemical, biochemical and bioassay data gathered since these first observations, support the concept that the nicotine-derived NNN and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) contribute significantly to the carcinogenic activity of snuff and cigarette smoke. Reactive metabolites of nicotine may also be carcinogenic factors. This hypothesis requires exploration.