In 1876, Lautenbach observed that the toxic effects of nicotine, administered to a dog, were reduced following passage through the liver. These experiments probably represent the first scientific investigation of nicotine pharmacology, toxicity, distribution and metabolism in the sense that we understand these terms today. However, it was some considerable time before Werle and Uschold (1948) described the detoxification of nicotine by the guinea-pig liver in vitro and this report seems to represent a reawakening of interest in the metabolism of the compound, which is one of the most widely used drugs in human society, and coincides with the beginning of the detailed biochemical investigation of drug metabolism in mammals. These first experiments used rather crude methods whereas in more recent years the use of compounds labelled with radioactive isotopes has resulted in considerable progress in the field. In particular, Larson and his group, (Larson and Silvette, 1968), have used radiochemical methods with outstanding success in evaluating nicotine metabolism in the mammalian body and this can be thought of as the third period of research into nicotine metabolism. It is important to realise that most of these experiments were performed before the impact of the statistical-epidemiological connection between certain diseases and tobacco smoking had made its full impact upon the scientific community, and we can only speculate on the reasons which encouraged these early authors to investigate nicotine metabolism. Presumably it was simply their professional curiosity as the study of the metabolism of foreign compounds became more interesting. The statistical correlation between cigarette smoking and the spread of bronchial carcinoma in the population (Wynder, 1952) led to a steadily growing interest in the mechanism of this phenomenon, and the publication of the Terry Report (1964) released an avalanche of activity both in basic and epidemiological research promoted, to a large extent, by a substantial increase in the funds available for this type of research. Thousands of publications have appeared since that time, although perhaps to the surprise of many pharmacologists and biochemists, the early results of the scientists mentioned above have, to a large extent, remained undisputed and have certainly not been discarded. Of course, other results, including many important details, have been added to these early results on which we still rely. In this paper, the present state of knowledge of the metabolic fate of nicotine will be reviewed in detail. This compound, which pharmacologically, is the most active constituent of tobacco smoke, is, in the opinion of this author, the main reason for the tobacco smoking habit. However, most species of tobacco plant contain alkaloids in addition to nicotine (e.g. nornicotine, anabasine, myosmine and nicotyrine) and these may all contribute to the taste and pharmacological actions of tobacco smoke. However, examination of their potential for pharmacological activity reveals that they are much less active than nicotine (Clark et al. 1965 ; Schievelbein, 1962; Werle and Schievelbein, 1961, 1962). In preparing this review, the author has attempted to restrict himself to results which are pertinent to the action of nicotine in the human organism receiving doses of the drug similar to those found in smokers. This is not always possible however, since results from human studies are very limited and, therefore, results from studies in experimental ani-