Tobacco addiction and chronic pain represent 2 highly prevalent and comorbid conditions that engender substantial burdens upon individuals and systems. Interrelations between pain and smoking have been of clinical and empirical interest for decades, and research in this area has increased dramatically over the past 5 years. We conceptualize the interaction of pain and smoking as a prototypical example of the biopsychosocial model. Accordingly, we extrapolated from behavioral, cognitive, affective, biomedical, and social perspectives to propose causal mechanisms that may contribute to the observed comorbidity between these 2 conditions. The extant literature was 1st dichotomized into investigations of either effects of smoking on pain or effects of pain on smoking. We then integrated these findings to present a reciprocal model of pain and smoking that is hypothesized to interact in the manner of a positive feedback loop, resulting in greater pain and increased smoking. Finally, we proposed directions for future research and discussed clinical implications for smokers with comorbid pain disorders. We observed modest evidence that smoking may be a risk factor in the multifactorial etiology of some chronically painful conditions and that pain may come to serve as a potent motivator of smoking. We also found that whereas animal studies yielded consistent support for direct pain-inhibitory effects of nicotine and tobacco, results from human studies were much less consistent. Future research in the emerging area of pain and smoking has the potential to inform theoretical and clinical applications with respect to tobacco smoking, chronic pain, and their comorbid presentation. (PsycINFO Database Record (c) 2011 APA, all rights reserved).