The heart reacts to stress through a variety of genetic responses. RNA is normally used by cells to make proteins. Tiny fragments of RNA, called microRNA, regulate this process. This unique property allows microRNAs to regulate a myriad of cellular events. We studied a particular microRNA called miR-499, which is found in heart and skeletal muscle. In experiments with transgenic mice, we found that elevated levels of miR-499 caused heart cells to enlarge, resulting in cardiac dysfunction. Our findings indicate that miR-499 may cause the heart to adjust its reaction to stress by regulating genes that are activated rapidly in response to cellular stimuli.