Migraine is a multifactorial and disabling syndrome often in comorbidity with psychiatric illnesses. Triptans are the first-line treatment in acute attacks and the most effective drugs in various types of migraine. Sumatriptan was the first medication of this group. Thanks to multiple types of formulations that greatly increase patient's compliance, sumatriptan is so far the most commonly used drug for moderate-to-severe acute migraine attacks. Although generally safe and well tolerated, sumatriptan has to be carefully administered in patients suffering from various types of medical conditions (such as cardiovascular and cerebrovascular disease and some psychiatric illnesses) and/or treated with various medications (such as monoamine oxidase inhibitors and selective serotonin reuptake inhibitors). The administration of sumatriptan in some psychiatric condition in which serotonin plays an important role (i.e., major depressive disorder and obsessive-compulsive disorder) has been underestimated so far. In fact, at present, literature studies are few, with non-conclusive and often contrasting findings. Thus, sumatriptan should continue to be used with caution in patients diagnosed with psychiatric illness and/or treated with drugs where serotonin is crucially involved in, until further data demonstrating complete safety become available.