Many patients with psychiatric disorders do not obtain remission from available pharmacological and psychotherapeutic treatments. Recent studies have demonstrated that there is a role for the rational use of 'combination therapy' when treating patients with serious and treatment-resistant mental illnesses. When prescribing multiple medications, it is easy, however, to fall into irrational polypharmacy. We present a framework that clinicians can use to avoid the pitfall of irrational polypharmacy. When using combination therapy, clinicians should consider: (a) pharmadynamic redundancy; (b) pharmacodynamic interactions; (c) pharmacokinetic interactions; and (d) avoid inadequate dosing of medications. Clinicians should also (e) regularly reassess the need for and benefit of continued combination therapy.