On page 40, Faria et al. establish the mechanism of action of N3′-P5′ phosphoramidate (NP) oligonucleotides, which belong to a new generation of antisense reagents that have considerable promise as therapeutic reagents, as shown in a number of in vivo studies. Their extremely high nuclease resistance and tight binding to single-stranded RNA initially piqued the interest of researchers; however, whether they exert their effect directly on mRNA or by interacting with other cellular components, as has been shown for some other types of therapeutic antisense reagents, was until now unclear. Faria et al. established a reporter system to examine whether the oligo acted by binding to its target sequence upstream of the luciferase gene. In both cell culture and skeletal muscles in vivo, the oligos acted by steric blockage of translation initiation, and not by inducing RNase H, another common mechanism of antisense reagents (see also p. 17).