Interstitial and perivascular fibrosis is a hallmark of adverse cardiac remodeling in response to stress such as hypertension, valve disease, or myocardial infarction. The cross talk between fibroblasts and cardiomyocytes seems to be a major determinant of the hypertrophic response, and fibroblasts may prove to be essential regulators of cardiac remodeling. The present review summarizes current knowledge on the modulation of myocardial fibrosis by microRNAs (miRNAs), single-stranded molecules consisting of approximately 22 noncoding nucleotides that regulate a variety of target genes involved in cardiovascular (patho)physiology. Dissection of miRNA-mediated mechanisms on myocardial and cellular and subcellular levels will provide insights into the impact of miRNAs for cardiac structural changes induced by different stressors and also expand our understanding of the interdependence of different cell types in the heart with regard to extracellular matrix formation during healing and remodeling after myocardial infarction or in response to pressure overload. The first successful treatment of fibrosis and failure in a murine pressure overload model by application of miRNA antagonists such as antagomirs in vivo raises the hope that manipulating miRNAs may emerge as a novel treatment strategy for fibrotic changes not only in the heart but also in other organs.