Sonic hedgehog (Shh) is secreted during neural tube (NT) development from the notochord to specify different progenitors in a concentration-dependent manner through the activity of activator (GliA) and repressor (GliR) forms of the Gli proteins. Andrew McMahon's group - using a combined genetic and bioinformatics approach to identify novel Gli targets during NT patterning -now suggest on p. 1977 that, surprisingly, GliA and GliR differ in their selection of target binding sites. Gli1-directed chromatin immunoprecipitation products were screened against genomic tiling arrays of putative Hedgehog targets(predicted from transcriptional profiling studies) to reveal both known and novel Shh-Gli targets, such as Nkx2.2 and Rab34,respectively. These targets were then validated by bioinformatics, expression studies in cell culture and transgenic experiments. Along the way, the authors have developed an algorithm that improves current in silico target prediction methods and the authors suggest that their approach could expand our understanding of transcriptional regulation in other developmental settings.