Abstract: Mutant mitochondrial DNA (mtDNA) gives rise to a broad range of heritable clinical syndromes (1). A cure for those affected remains out of reach (1). However, recently developed mitochondrial replacement therapy (MRT) has raised the prospect of disease-free progeny for women carriers (2–4). Moreover, the feasibility of replacing mutant oocytic or zygotic mtDNA with a donated wild-type counterpart in humans has now been firmly established (2–4). In the United Kingdom, legislation regulating the clinical application of MRT, now 10 years in the making, has recently been approved by the House of Commons (5) and the House of Lords (6). The regulatory vetting of MRT in the United States, under way for a year, remains a work in progress (7). Here, we compare and contrast the regulatory history of MRT in the United Kingdom and the United States and examine potential lessons learned.