Of the thousands of proven carcinogens and toxic agents contained within a cigarette, nicotine, while being the addictive agent, is often viewed as the least harmful of these compounds. Nicotine is a lipophilic molecule whose effects on neuronal nicotinic acetylcholine receptors (nAChR) have been primarily focused on its physiologic impact within the confines of the brain and peripheral nervous system. However, recently, many studies have found neuronal nAChRs to be expressed on many different nonneuronal cell types throughout the body, where increasing evidence suggests they have important roles in determining the consequences of nicotine use on multiple organs systems and diseases as diverse as ulcerative colitis, chronic pulmonary obstructive disease, and diabetes, as well as the neurologic disorders of Parkinson's and Alzheimer's disease. This review highlights current evidence for the expression of peripheral nAChRs in cells other than neurons and how they participate in fundamental processes, such as inflammation. Understanding these processes may offer novel therapeutic strategies to approach inflammatory diseases, as well as precautions in the design of interventional drugs.