Comorbid migraine in the course of bipolar disorder has been reported as highly prevalent and associated with increased morbidity. Patients with bipolar disorder and comorbid migraine tend to present with higher rates of rapid cycling, increased number of depressive episodes, more severe depression, and increased suicidality when compared to subjects with bipolar disorder alone. Both conditions display similar clinical features, such as relapsing-recovering presentation, and vulnerability to psychological and physical stress. Clinical implications of this association have been well established, however the biological underpinnings involved in both conditions remain poorly understood. Inflammation and oxidative and nitrosative stress seem to play a role as mediators in the cross-sensitization between bipolar disorder and migraine. Therefore, the present study aims to review the role of inflammation, oxidative and nitrosative stress as underlying mechanisms in the natural history of bipolar disorder comorbid with migraine.