The Human Genome Project marked a major milestone in the scientific community as it unravelled the ~3 billion bases that are central to crucial aspects of human life. Despite this achievement, it only scratched the surface of understanding how each nucleotide matters, both individually and as part of a larger unit. Beyond the coding genome, which comprises only ~2% of the whole genome, scientists have realized that large portions of the genome, not known to code for any protein, were crucial for regulating the coding genes. These large portions of the genome comprise the ‘non-coding genome’. The history of gene regulation mediated by proteins that bind to the regulatory non-coding genome dates back many decades to the 1960s. However, the original definition of ‘enhancers’ was first used in the early 1980s. In this Review, we summarize benchmark studies that have mapped the role of cardiac enhancers in disease and development. We highlight instances in which enhancer-localized genetic variants explain the missing link to cardiac pathogenesis. Finally, we inspire readers to consider the next phase of exploring enhancer-based gene therapy for cardiovascular disease.