An important goal of biomedical research is to translate basic research findings into useful medical advances. In the field of neuropharmacology this requires understanding disease mechanisms as well as the effects of drugs and other compounds on neuronal function. Our hope is that this information will result in new or improved treatment for CNS disease. Despite great progress in our understanding of the structure and functions of the CNS, the discovery of new drugs and their clinical development for many CNS disorders has been problematic. As a result, CNS drug discovery and development programs have been subjected to significant cutbacks and eliminations over the last decade. While there has been recent resurgence of interest in CNS targets, these past changes in priority of the pharmaceutical and biotech industries reflect several well-documented realities. CNS drugs in general have higher failure rates than non-CNS drugs, both preclinically and clinically, and in some areas, such as the major neurodegenerative diseases, the clinical failure rate for disease-modifying treatments has been 100%. The development times for CNS drugs are significantly longer for those drugs that are approved, and post-development regulatory review is longer. In this introduction we review some of the reasons for failure, delineating both scientific and technical realities, some unique to the CNS, that have contributed to this. We will focus on major neurodegenerative disorders, which affect millions, attract most of the headlines, and yet have witnessed the fewest successes. We will suggest some changes that, when coupled with the approaches discussed in the rest of this special volume, may improve outcomes in future CNS-targeted drug discovery and development efforts. This article is part of the Special Issue entitled "Beyond small molecules for neurological disorders".