Refractory migraine (RM) headaches pose important treatment challenges to the patients who live with them and the clinicians who try to treat them. Defined based on the lack of response to acute, preventive, and nonpharmacologic treatment, RM is often treated with a combination of treatments. Although combination therapy for RM has not been systematically studied in randomized trials, clinical experience suggests that a rational approach to RM treatment, utilizing a combination of treatments, may be effective where monotherapy has failed. In this article we briefly identify patient populations appropriate for more aggressive migraine prevention with combination therapy. We then discuss modifiable risk factors and comorbidities in migraine and then focus on the use of rational combination therapy, as well as the duration migraine preventatives should be considered for use. Future research is needed to evaluate the full potential of rational combination treatment as a strategy for treating and ultimately preventing RM.