Because the prevalence of smoking in the United States remains significantly high, it is important to determine a patient's smoking status and perform a complete medication history to assess for potential drug interactions with smoking. Tobacco smoke can increase the hepatic metabolism and can oppose the pharmacologic effects of certain drugs. This article reviews the clinically significant drug interactions, resulting primarily from the induction of cytochrome P450 enzymes by tobacco smoke, of which all acute and critical care providers need to be aware when making therapeutic decisions and recommendations.