Cardiovascular disease is the predominant cause of human morbidity and mortality in developed countries. Thus, extraordinary effort has been devoted to determining the molecular and pathophysiological characteristics of the diseased heart and vasculature with the goal of developing novel diagnostic and therapeutic strategies to combat cardiovascular disease. The collective work of multiple research groups has uncovered a complex transcriptional and posttranscriptional regulatory circuit, the integrity of which is essential for the maintenance of cardiac homeostasis. Mutations in or aberrant expression of various transcriptional and posttranscriptional regulators have now been correlated with human cardiac disease, and pharmacological modulation of the activity of these target genes is a major focus of ongoing research. Recently, a novel class of small noncoding RNAs, called microRNAs (miRNAs), was identified as important transcriptional and posttranscriptional inhibitors of gene expression thought to “fine tune” the translational output of target messenger RNAs (mRNAs). 1, 2 miRNAs are implicated in the pathogenesis of various cardiovascular diseases and have become an intriguing target for therapeutic intervention. This review focuses on the basic biology and mechanism of action of miRNAs specifically pertaining to cardiovascular disorders and addresses the potential for miRNAs to be targeted therapeutically in the treatment of cardiovascular disease. miRNA Processing and Function miRNAs originate from longer precursor RNAs called primary miRNAs that are regulated by conventional transcription factors and transcribed by RNA polymerase II. Primary miRNAs are hundreds to thousands of nucleotides long and are processed in the nucleus into an 70-to 100-nucleotide hairpin-shaped precursor miRNA by the RNase III enzyme Drosha and the double-stranded RNA binding protein DGCR8. The precursor miRNA is then transported into the cytoplasm by the nuclear export factor exportin 5 and further processed into an 19-to 25-nucleotide double-stranded RNA by the RNaseIII enzyme Dicer. This duplex miRNA is then incorporated into the RNA-induced silencing complex. One strand remains in the RNA-induced silencing complex and becomes the “mature” miRNA, whereas the other strand is often rapidly degraded and is called the “star” strand (miRNA*). On being loaded into the RNA-induced silencing complex, the mature miRNA associates with target mRNAs and acts as a negative regulator of gene expression by promoting mRNA degradation or inhibiting translation. 3 Translational inhibition seems to be the predominant mechanism in mammals; however, target genes that are strongly downregulated on the protein level often show a reduced mRNA level, 4 suggesting that mRNA destabilization is a major contributor to gene silencing. A mature miRNA typically regulates gene expression via an association with the 3 untranslated region (UTR) of an mRNA with complementary sequence, although emerging evidence suggests that miRNAs may also target 5 UTRs or exons and may potentially even undergo base pairing with regulatory DNA sequences to regulate transcription. On miRNA binding to a 3 UTR, the degree of mRNA degradation and/or translational repression is affected by multiple mechanisms, including the overall complementarity between the miRNA and target mRNA, the secondary structure of the adjacent sequences, the distance of the miRNA binding site to the coding sequence of the mRNA, and the number of target sites within the 3 UTR. 5 Complementarity between nucleotides 2 through 8 of the miRNA, called the …