PIP: The importance of environmental factors for drug metabolism has recently been established. This paper reviews the major environmental and nutritional sources of variation in drug response. Environmental variables examined include drug interactions, alcohol, cigarette smoking, marijuana, other socially used drugs, steroid oral contraceptives (OCs), and agricultural industrial contaminants. Drug-drug interactions act chiefly by induction or inhibition of the microsomal metabolizing enzyme system. The effect of alcohol on the metabolism of other drugs depends on the drug, the dose of alcohol, the duration of exposure, and possibly diet and the presence of disease. Cigarette smoke affects the biotransformation of several drugs, and smokers often require higher doses of oxidized drugs. An additive effect of cigarette smoke and marijuana has been observed, resulting in the halving of the half-life of some drugs. Caffeine may serve as a competitive inhibitor of microsomal enzymes. Chemical pollutants such as chlorinated and polycyclic hydrocarbons can alter the hepatic drug metabolizing enzyme activity. The nutritional variables examined include malnutrition, anemia, vegetarian diets, dietary contaminants, and specific microconstituents of diet. Total dietary protein has a more critical effect on drug metabolism than fat or carbohydrate. These findings indicate that many factors in each patient are capable of altering drug response. Assessment of these variables permits more rational prescribing practices. For example, most patients over age 70 or vegetarian OC users require half the usual dosage of most drugs, whereas smokers and industrial workers require higher than recommended doses. Plasma measurements are of value in such assessments. Developing countries are advised to encourage rational use of a restricted number of drugs through an understanding of the sources of variation in drug response. This requires communication between clinical pharmacologists, other clinicians, pharmacists, government agencies, and patients. A prescriber's formulary tailored to local needs is an essential component of any plan to improve drug therapy.