The first antidepressants were created by chance but brought the idea that central serotonin agonism produced an antidepressant effect. SSRIs were the first class of psychotropic medications to be rationally designed, meaning that researchers intended to utilize a specific mechanism of action while avoiding adverse effects. In this way, SSRIs were created to be safer and more tolerable than previous antidepressants. SSRIs share many similarities, but differ in terms of pharmacokinetics and effects on CYP450 enzymes, which is detailed in this chapter. Further information will be provided regarding safety, clinical indications/uses, and dosing recommendations.