Smoking produces profound changes in physiology beyond those associated with the delivery of nicotine to the bloodstream. It has long been known that these changes put patients at risk for heart disease, cancers, and lung diseases. More recently, it has been discovered that smoking is a risk factor for chronic pain. Robust epidemiological evidence is showing that smokers not only have higher rates of chronic pain but also rate their pain as more intense than nonsmokers. Because the relationship between smoking and pain is of relevance to clinicians in many specialties, researchers at Mayo Clinic are examining this relationship in depth. This article describes some of what they and others have discovered in recent years about the interactions between smoking and chronic pain.