BACKGROUND: Gene mutations are responsible for a sizeable proportion of cases of heart failure. However, the number of patients with any specific mutation is small. Repositioning of existing US Food and Drug Administration-approved compounds to target specific mutations is a promising approach to efficient identification of new therapies for these patients. METHODS: The National Institutes of Health Library of Integrated Network-Based Cellular Signatures database was interrogated to identify US Food and Drug Administration-approved compounds that demonstrated the ability to reverse the transcriptional effects of RESULTS: Several angiotensin receptor blockers were identified from our in silico screen. Of these, olmesartan significantly elevated the expression of sarcomeric genes and rate and force of contraction and ameliorated arrhythmogenic potential. In addition, olmesartan exhibited the ability to reduce phosphorylation of extracellular signal-regulated kinase 1 in CONCLUSIONS: In silico screening followed by in vitro validation with induced pluripotent stem cell-derived models can be an efficient approach to identifying repositionable therapies for monogenic cardiomyopathies.