Migraine and obesity are associated in several ways. First, both are prevalent and disabling disorders influenced by genetic and environmental risk factors. Second, migraine with aura, as obesity, seems to be a risk factor for cardiovascular events. Finally, large population-based studies suggest that obesity is a risk factor for chronic migraine after adjusting for comorbidities. In this article, we discuss plausible mechanisms that may account for this association. Several of the inflammatory mediators that are increased in obese individuals are important in migraine pathophysiology, including interleukins and calcitonin gene-related peptide (CGRP). These mediators may increase the frequency, severity, and duration of migraine attacks per se, which in turn would cause central sensitization. Repeated central sensitization may be associated with permanent neuronal damage close to the periaqueductal gray area, with poor modulation to pain. Obesity is also a state of sympathetic activation, which may contribute to increase in headache frequency. Furthermore, the levels of adiponectin are decreased in obesity. At low but not normal levels, adiponectin is nociceptive. Shared biologic predisposition may also play a major role. Orexins modulate both pain and metabolism. Dysfunction in the orexins pathways seems to be a risk factor for both conditions. Finally, conditions that are comorbid to both states (e.g., depression, sleep apnea) may also make the relationship between both diseases more complex.