Large numbers of noncoding RNA transcripts (ncRNAs) are being revealed by complementary DNA cloning and genome tiling array studies in animals. The big and as yet largely unanswered question is whether these transcripts are relevant. A paper by Willingham et al. shows the way forward by developing a strategy for large-scale functional screening of ncRNAs, involving small interfering RNA knockdowns in cell-based screens, which identified a previously unidentified ncRNA repressor of the transcription factor NFAT. It appears likely that ncRNAs constitute a critical hidden layer of gene regulation in complex organisms, the understanding of which requires new approaches in functional genomics.