AbstractMicroRNAs (miRNAs) negatively regulate gene expression at the post‐ transcriptional level, primarily by base‐pairing with the 3′‐untranslated region (3′‐UTR) of their target mRNAs. Many miRNAs are expressed in a tissue/organ‐specific manner and are associated with an increasing number of cell proliferation, differentiation, and tissue development events. Cardiac muscle expresses distinct genes encoding structural proteins and a subset of signal molecules that control tissue specification and differentiation. The transcriptional regulation of cardiomyocyte development has been well established, yet only until recently has it been uncovered that miRNAs participate in the regulatory networks. A subset of miRNAs are either specifically or highly expressed in cardiac muscle, providing an opportunity to understand how gene expression is controlled by miRNAs at the post‐transcriptional level in this muscle type. miR‐1, miR‐133, miR‐206, and miR‐208 have been found to be muscle‐specific, and thus have been called myomiRs. The discovery of myomiRs as a previously unrecognized component in the regulation of gene expression adds an entirely new layer of complexity to our understanding of cardiac muscle development. Investigating myomiRs will not only reveal novel molecular mechanisms of the miRNA‐mediated regulatory network in cardiomyocyte development, but also raise new opportunities for therapeutic intervention for cardiovascular disease. WIREs Syst Biol Med 2011 3 183–190 DOI: 10.1002/wsbm.111This article is categorized under: Developmental Biology > Developmental Processes in Health and Disease