We would like to comment on a recent study that analyzed the role of microRNA-21 (miR-21) in a mouse model of cardiac disease (1). Using miR-21–deficient mice and novel, very short, 8-nucleotide anti–miR-21 oligonucleotides, the authors failed to detect any modulation of pressure overload-induced myocardial hypertrophy and fibrosis and concluded that miR-21 plays no role in cardiac disease. In contrast, we and others reported that inhibition of miR-21 with highly specific, 22-and 15-nucleotide-long anti–miR-21 oligonucleotides effectively inhibits myocardial and pulmonary fibrosis (2, 3). While genetic deletion of a target may lead to compensation during development and is often different from pharmacological inhibition of this target in the adult organism, the discrepancy between the therapeutic trials using long versus short 8-mer oligonucleotides is striking. We therefore carried out a direct head-to-head comparison of three different oligonucleotide chemistries (Figure 1A) in the same model of pressure overload-induced cardiac hypertrophy (transaortic constriction [TAC]). The two 22-mer oligonucleotides were complementary to the full-length miR-21, while the 8-mer was complementary to nucleotides 2 to 9 of miR-21, locked nucleic acid modified (LNA modified), and identical to the oligonucleotide used in the report by Patrick et al.(Figure 1A).