Despite great advances in basic neuroscience knowledge, the improved understanding of brain functioning has not yet led to the introduction of truly novel pharmacological approaches to the treatment of central nervous system (CNS) disorders. This situation has been partly attributed to the difficulty of predicting efficacy in patients based on results from preclinical studies. To address these issues, this review critically discusses the traditional role of animal models in drug discovery, the difficulties encountered, and the reasons why this approach has led to suboptimal utilization of the information animal models provide. The discussion focuses on how animal models can contribute most effectively to translational medicine and drug discovery and the changes needed to increase the probability of achieving clinical benefit. Emphasis is placed on the need to improve the flow of information from the clinical/human domain to the preclinical domain and the benefits of using truly translational measures in both preclinical and clinical testing. Few would dispute the need to move away from the concept of modeling CNS diseases in their entirety using animals. However, the current emphasis on specific dimensions of psychopathology that can be objectively assessed in both clinical populations and animal models has not yet provided concrete examples of successful preclinical-clinical translation in CNS drug discovery. The purpose of this review is to strongly encourage ever more intensive clinical and preclinical interactions to ensure that basic science knowledge gained from improved animal models with good predictive and construct validity readily becomes available to the pharmaceutical industry and clinical researchers to benefit patients as quickly as possible.