When first introduced, antisense oligonucleotides were hailed as the long awaited magic bullet that would provide an unprecedented level of specificity in controlling gene expression. Following this initial enthusiasm, antisense oligonucleotides have been maligned as nonspecific, toxic, and essentially useless. However, application of antisense oligonucleotide technology in the nervous system stands apart from the use of this technique in peripheral systems, largely because of its enormous success. The source of this success remains a matter of some controversy. This text addresses the origins of that controversy and determines whether the nervous system is a privileged site for antisense oligonucleotide action an d not subject to the same vagaries and pitfalls as non-neuronal systems. It contains chapters by experts in the field that focus on the use of this technique in a variety of behavioural systems, as well as rapid and nonspecific effects and the uptake and metabolism of antisense oligonucleotides by the nervous system.