Dilated cardiomyopathy (DCM) represents the leading cause of mortality in patients with muscular dystrophy (MD). Standard pharmacological treatments are unable to combat the underlying genetic defects that result in chronic myocardial wasting and fibrotic infiltration. Alternative strategies to treat DCM are under intense investigation including gene and cell therapy approaches. Although currently the most promising, gene therapy approaches directed at treating the heart must carefully consider the choice of vector, gene replaced, and delivery method. Challenges may include accommodating transgene size (eg, Dystrophin), and avoiding potential immunity to the transgene and/or viral capsid. As a target for therapy, microRNAs (miRNAs) offer advantages that evade both of these challenges. MicroRNAs are short noncoding RNAs that modify gene expression by regulating mRNA stability or translation during various developmental or disease processes. 1 Within the past decade miRNAs have been shown to play a key role in regulating the progression of cardiomyopathy and as a result have become genetic targets for therapy. 1 Encouraging results in preclinical studies have led to the integration of miRNAs into clinical trials. To date, the majority of this inclusion has focused on miRNA expression signatures that are used as biomarkers for disease progression and readouts of therapeutic efficacy for other therapies, as opposed to a miRNA-targeted therapy. 2 There has been one miRNA product, Miravirsen, which has reached the clinic for treatment of hepatitis C virus (HCV) infection as an anti-miR of miR-122, a hepatic-specific miRNA that directly targets HCV. 3 Miravirsen showed dose-dependent efficacy in chronic HCV-infected patients without dose-dependent adverse events. 3 This trial, along with impending trials using miRNA-based therapies for cancer, 2 provide valuable safety data that can be applied to future trials for DCM. The potential for a common miRNA therapy that can be applied to multiple forms of muscular dystrophy (MD) with a severe cardiomyopathy component has become an attractive option. The degenerative process in muscle indicative of MDs is often thought of as the result of a common origin; however, caution must be taken when considering a universal approach to treat DCM. This is evidenced in this issue of JAHA by Quattrocelli et al4 and in previous studies from the Sampaolesi group showing that not all dystrophies complicated by DCM arise from a common pathway or follow the same progression. Nonetheless, the potential power of a miRNA-based approach is indisputable as demonstrated by Quattrocelli et al. 4 This sets the stage for long-term treatments for DCM particularly when the miRNA target is well defined and preclinical safety and efficacy is established in the model for the disease it is intended to treat.