There is growing pressure to find more effective therapies for major psychiatric disorders, such as schizophrenia and depressive disorder. The repeated disappointments that have been experienced with highly selective, single-target agents have prompted questions about their relative merits. In contrast, a multi-target agent (MTA) approach, discovered either by serendipity or by judicious design, might offer a more rational way to address the complex clinical demands of patients and their co-morbidities. Rather than being mutually exclusive, a balanced portfolio of the two approaches may offer a beneficial and synergistic outcome toward identification of novel antipsychotic and antidepressant therapies. With improvements in biomarker technology, translational biology and a growing understanding of psychopathology, there is optimism that the new generation of MTAs will finally shed the stigma of 'dirty drugs' and progress to the concept of intentionally designed and tailored psychopharmacological agents.