The Journal is publishing three multiple-medication trials for three different diagnoses in this issue. One article describes the Combining Medications to Enhance Depression Outcomes study (CO-MED), which tested three comparison arms (one antidepressant alone and two different antidepressant combinations) in 665 individuals with depression to contrast combination-drug with single-drug treatment for depression; the study found no differences, and therefore no support for polypharmacy, between the three groups in outcomes. Another study of 150 individuals with alcohol dependence contrasted one treatment (naltrexone) either alone or in combination with a second drug (gabapentin) and compared both to double placebo; the study showed that the combination of drugs was better than either of the single treatments or placebo during the initial phase of treatment, therefore partially supporting polypharmacy. The third study, evaluating 127 individuals with schizophrenia, compared the effectiveness of switching from polypharmacy to monotherapy in half of the participants; this study showed a significant risk of study failure in the switch (monotherapy) group, despite the presence of fewer side effects, an outcome supportive of polypharmacy. These trials represent well-designed treatment comparisons in different diagnostic groups, testing single or multiple medications. We can have confidence in the outcomes given the rigor of their designs. These trials suggest that the answer to the question of whether polypharmacy is good treatment will be specific to the combination and to the diagnosis. There seems not to be an easy or a universal answer to this treatment question.