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Polypharmacy is defined as using two or more drugs in treatment of one disorder. It might be considered as a “rule” rather than “exception” in psychiatry. The National Association of State Mental Health Program Directors (NASMHPD) categorized polypharmacy as follows in 2001 NASMHPD Technical Report: “same class polypharmacy,” such as using two SSRIs in a case of depression; “multi-class polypharmacy” (e.g. use of a mood stabilizer like valproate along with an atypical antipsychotic, such as olanzapine, for treatment of mania); “adjunctive polypharmacy” (e.g. treating insomnia caused by bupropion with trazodone); “augmentation polypharmacy” refers to the use of one medication at a lower than normal dose along with another medication from a different class in full therapeutic dose for the same symptom cluster (e.g. addition of low dose haloperidol in a patient responding to risperidone alone only partially); or addition of a medication that would not be used alone for the same symptom cluster (e.g. augmentation of antidepressants with lithium or thyroid hormone), and finally “total polypharmacy” which means using more than two medications in the identical pharmacological category for the same condition at the same time. Polypharmacy has become a common clinical practice for many psychiatric conditions. Up to one-third of the patients visiting outpatient psychiatry clinics have been found to be on three or more psychotropic medications. Polypharmacy could increase medical risks (adverse effects, drug and food-interactions, morbidity, mortality, etc. ) and decrease quality of lives of the patients receiving it. Polypharmacy should be considered only after monotherapy has been tried and failed. It should also be based on evidence (when available) in addition to knowledge of mechanisms of action, pharmacodynamics, and pharmacokinetics of medications and should always keep the risk versus benefit ratio in perspective. At times polypharmacy is applied based on anecdotal or personal clinical experience, which would be non-scientific and risky, but it should be rational and valid based on good evidence such as adding lithium in a treatment resistant depression case, which has been proven to be effective in several double blind controlled studies. When rational polypharmacy can address treatment resistance, then quality of life of the patients would be improved. However, irrational use of polypharmacy in practice poses very serious risks even death and might result in irreversible damage or morbidity to our patients. Moreover, irrational polypharmacy practices also wastes limited resources, can increase pharmacoeconomic costs, and may result in lawsuits. The principles of rational polypharmacy should be built on a solid knowledge and training on psychiatry and psychopharmacology. In addition, clinicians should update their knowledge, clinical skills, and abilities regularly by attending to psychopharmacology lectures, conferences, workshops, courses, etc. delivered by experts in their field throughout their careers.