This paper presents 2 case scenarios that illustrate the complexity of diagnosing and managing migraine associated with hormonal changes. Migraine is commonly associated with comorbidies such as depression, anxiety, obesity, cardiovascular disease, as well as other conditions, thereby making management more challenging for the physician and the patient. The first case is a 35-year-old woman who has migraine almost exclusively during menstruation. She is under a physician's care for long-term management of premenstrual dysphoric disorder (PMDD). Achieving a differential diagnosis of pure menstrual migraine is illustrated, and a detailed treatment plan including use of a migraine miniprophylaxis protocol, management of her PMDD, and prescription of acute treatment medications is reviewed. The second case scenario describes the diagnosis of menstrually associated migraine in a woman who suffers from a frequent disabling migraine along with work-related anxiety and depression. This paper reviews her differential diagnosis, laboratory testing, treatment plan, including management of her comorbid anxiety and depressive symptoms.