Combination pharmacotherapy for bipolar disorder is commonplace and often reflects the severity and complexity of the illness and the comorbid conditions frequently associated with it. Across treatment settings, about one-fifth of patients with bipolar disorder appear to receive four or more psychotropic medications. Practice patterns often outpace the evidence-based literature, insofar as few systematic studies have examined the efficacy and safety of two or more medications for any given phase of illness. Most randomized trials of combination pharmacotherapy focus on the utility of pairing a mood stabilizer with a second-generation antipsychotic for prevention of either acute mania or relapse. In real-world practice, patients with bipolar disorder often take more elaborate combinations of mood stabilizers, antipsychotics, antidepressants, anxiolytics, stimulants, and other psychotropics for indefinite periods that do not necessarily arise purposefully and logically. In this article, I identify clinical factors associated with complex combination pharmacotherapy for patients with bipolar disorder; describe approaches to ensuring that each component of a treatment regimen has a defined role; discuss the elimination of unnecessary, ineffective, or redundant drugs in a regimen; and address complementary, safe, rationale-based drug combinations that target specific domains of psychopathology for which monotherapies often provide inadequate benefit.Copyright © 2019 by the American Psychiatric Association.