This column is the second in a series on central nervous system (CNS) drug development. The goal of this series is to explain to practicing clinicians how drugs are developed and why CNS drug development is at an important juncture involving both significant challenges and opportunities. This column (Part 2) reviews the history of CNS drug development from the 1960s to the 1990s. During the 1960s, researchers acquired a much clearer understanding of basic CNS pharmacology (e.g., biogenic amine transmitter systems in the brain) and developed the first animal models of psychiatric illness that could be used to test potential psychiatric medications. During the 1970s, drug development scientists used their expanded understanding of receptor binding affinity and the theories and techniques developed in the 1950s and 1960s to produce new CNS-active medications. They did this by adding or reducing affinities for certain regulatory proteins (e.g., receptors) to increase positive effects and/or minimize adverse effects. The development of newer antipsychotics and antidepressants is discussed to illustrate this process. The next column in this series will review CNS drug development during the first decade of the 21st century and discuss what directions we can expect the field to take in the next 10 to 20 years.