Obesity and smoking are important causes of morbidity and mortality worldwide. The diseases and conditions associated with smoking make tobacco use one of the leading causes of death worldwide. In the World Health Organization European region, overweight and obesity are responsible for many chronic diseases, causing more than one million deaths each year. Smoking cessation is associated with a significantly reduced mortality risk in every body-mass-index group. Reductions in smoking and obesity would increase both the psychophysical well-being of the population and its economic productivity; it would also reduce the direct costs of pharmacological therapies and other forms of treatment. The aim of this review is to critically evaluate how tobacco smoking and obesity interact to reduce life expectancy, and to offer a comprehensive view of this issue that should be useful for clinical practice.