Growing evidence indicates that microRNAs (miRNAs) are involved in a variety of basic biological processes, including cell proliferation, apoptosis, stress response, hematopoesis, and oncogenesis. In fact, bioinformatic analysis predicts that each miRNA may regulate hundreds of targets, suggesting that miRNAs may play roles in almost every biological pathway. Information from recent studies indicate that miRNAs are involved in the regulation of cardiac development and pathophysiology. Notably, knockout of miRNA-1 was associated with cardiac defects, including regulation of cardiac morphogenesis, electrical conduction, and cell cycle control. Our group has identified a critical role of miRNA-1 and miRNA-133 in determining cardiac hypertrophy and has shown an inverse correlation of expression with cardiac hypertrophy, in vitro, in murine models and in human disease states associated with cardiac hypertrophy. Remarkably, in vivo experiments with a single infusion of antagomir-133 oligonucleotide, a small cholesterol-conjugated RNA sequence suppressing endogenous miRNA, induced marked and sustained cardiac hypertrophy. Shedding light on the role of this new class of RNA molecules in heart physiology and pathology may reveal possible future therapeutic applications for the treatment of heart diseases.