MicroRNAs (miRNAs) are potent regulators of mRNA stability and thereby protein expression. As such, miRNAs have become of interest as possible therapeutics and/or therapeutic targets. In this context, small complementary miRNA sequences known as antagomirs could be used to inhibit miRNA activity, while miRNA mimics could confer gain-of-function activity. However, a note of caution is sounded by Patrick et al. in this issue of the JCI, as they show that although recent reports have suggested that an miR-21 antagomir might be therapeutically useful in preventing heart failure in mice, genetic deletion of miR-21 does not confer a similar phenotype, suggesting possible confounding factors that are only now beginning to be revealed in the techniques used to study miRNA biology.