Disorders of the central nervous system (CNS) are some of the most prevalent, devastating and yet poorly treated illnesses. The development of new therapies for CNS disorders such as Alzheimer's disease has the potential to provide patients with significant improvements in quality of life, as well as reduce the future economic burden on health-care systems. However, few truly innovative CNS drugs have been approved in recent years, suggesting that there is a considerable need for strategies to enhance the productivity of research and development in this field. In this article, using illustrative examples from neurological and psychiatric disorders, we describe various approaches that are being taken to discover CNS drugs, discuss their relative merits and consider how risk can be balanced and attrition reduced.