MicroRNAs (miRNAs) provide a recently recognized mechanism to control protein abundance. These small RNA molecules bind to mRNAs and inhibit translation or promote degradation of the RNA. Zhao et al. present evidence for an important role of miRNA in heart development. They selected for study two miRNAs known as miR-1-1 and miR-1-2 that are expressed in the developing heart and conserved from flies to humans. Reporter assays in transgenic animals revealed that the miR-1-1 and miR-1-2 enhancer regions were bound by key muscle-related transcription factors, including SRF (serum response factor), and enhanced expression of the miRNAs in certain cells. The authors also developed a method focused on target accessibility rather than primary sequence, which allowed them to detect possible target mRNAs. Along with other factors, predictions of free energy (ΔG) were used to locate unstable sites in 3′ untranslated regions of mRNA targets characteristic of known miRNA binding sites. This allowed identification of the Hand2 gene, a mutation of which causes defects in proliferation of cardiac cells. Commentary by Bruneau raises important questions regarding the benefits and possible weaknesses of the target screen and regarding the role of miRNAs in signaling hierarchies. He wonders whether it would be simpler to regulate expression of the Hand gene itself. The answer seems likely to yield insight into how such regulatory networks permit fine regulation of organ growth and differentiation.