Knockout mice are the gold standard for understanding gene function-or are they? The phenotypes of Egfl7 knockout mice and morphant fish suggested a critical and unexpected role for this secreted protein in angiogenesis, but a highly conserved microRNA, miR-126, was subsequently found in intron 7 of the Egfl7 gene. Wang et al. used gene targeting to knock out miR-126, but not Egfl7, and found that loss of miR-126 alone causes defects in embryonic and postnatal angiogenesis. These observations suggested that miR-126, rather than Egfl7, is the key player in angiogenesis, a result confirmed in a parallel study by Kuhnert et al. (2008), who generated mice specifically lacking Egfl7, but not miR-126, and vice versa. The intimate spatial and transcriptional relationships between miRNAs and protein coding genes suggest that retrospective analysis of other gene-targeted mice may identify additional functions for noncoding RNAs.This PaperPick refers to " The Endothelial-Specific MicroRNA miR-126 Governs Vascular Integrity and Angiogenesis," by S. Wang, A.B. Aurora, B.A. Johnson, X. Qi, J. McAnally, J.A. Hill, J.A. Richardson, R. Bassel-Duby, and E.N. Olson, published in August 2008. Video Abstract: Drs. Wang and Olson discuss their work on miR-129, as well as the general idea that gene loci encoding both a protein and an intronic microRNA commonly share regulated expression patterns and downstream functions.