In 1964, the Surgeon General released a landmark report on the dangers of smoking. During the intervening 45 years, 29 Surgeon General’s reports have documented the overwhelming and conclusive biologic, epidemiologic, behavioral, and pharmacologic evidence that tobacco use is deadly. Our newest report, How Tobacco Smoke Causes Disease, is a comprehensive, scientific discussion of how mainstream and secondhand smoke exposures damage the human body. Decades of research have enabled scientists to identify the specific mechanisms of smoking-related diseases and to characterize them in great detail. Those biologic processes of cigarette smoke and disease are the focus of this report.