For decades, the standard of care for acute migraine attacks has offered us a jeopardized therapeutic choice on different pathways of action, such as 5HT1B/D for triptans and cyclooxygenase-1 (COX-1) for non-steroidal anti-inflammatory drugs (NSAIDs), creating potential drug–drug interactions (DDIs) and competitive metabolic destiny favoring adverse events (AEs). This evidence concerns the gene HTR1B and migraine disorder.