Recent studies have discovered novel and unexpected roles for microRNAs (miRNAs), which are small, non-coding, endogenously conserved RNAs. MicroRNAs typically act post-transcriptionally to repress target gene expression and have been estimated to affect most of the genome. They modulate cell growth and differentiation, signal transduction, organ development, and cell lineage specification, among others. MicroRNAs are expressed in the cardiovascular system and play a critical role in the development and function of the heart. We will discuss the novel molecular mechanisms of the miRNA-mediated regulatory network in heart development and the new opportunities for therapeutic intervention for cardiovascular disease.