This column is the second in a series exploring lessons for psychiatric drug development that can be learned from the development of 6 central nervous system drugs with novel mechanisms of action over the past 25 years. Part 1 presented a brief overview of the neuroscience that supported the development of each of these drugs, including the rationale for selecting their targets and indications. This column reviews specific principles involved in the development of these 6 drugs that have important implications for the future of psychiatric drug development. These include focusing on efficacy for a specific symptom or behavior rather than a broad syndrome, choosing a target in the brain with a specific behavioral output that is conserved from lower mammalian to human brains, and measuring outcomes based on behavioral phenomena that can be readily measured in an unambiguous parametric way. It is hoped that the Research Domain Criteria initiative of the National Institute of Health will promote research advances consistent with this model. © 2015 Wolters Kluwer Health, Inc.