Clustered regularly interspaced short palindromic repeats (CRISPR) has revolutionized many research areas and has rapidly become the gold standard in genome editing by outrivaling all other available tools. Its unprecedented versatility creates the opportunity to modify any aspect of gene regulation. Even though the cardiac field is starting to appreciate the potential of CRISPR, many applications to study cardiac biology and disease so far have remained untouched. In particular, CRISPR-based strategies that act independent of the homology-directed repair pathway could help circumvent issues of modifying the genome of postmitotic cardiomyocytes, which is currently limiting its utility in the heart. Here, we review current applications and future potential for the use of CRISPR to study cardiac biology and disease.