There have been many recent reports of receptor down-regulation in the brain by antisense oligodeoxynucleotides (ODNs) administered in vivo. However, the literature is inconsistent regarding the experimental criteria that are necessary or sufficient to demonstrate a true antisense effect. Here we review some of the critical conceptual and methodological issues. We highlight the problems of specificity and toxicity encountered in our attempts to down-regulate the 5-HT1A receptor using a phosphorothioate-modified ODN. We also present preliminary data suggestive of a decreased hippocampal 5-HT1AR expression induced by the antisense ODN, but it is a reduction which is of limited extent and which does not provide unequivocal evidence for an antisense-mediated effect. We conclude that antisense ODNs are not yet suitable as tools for routine in vivo neuropharmacological use, although they show considerable promise.