Despite the promising outcomes of the two techniques, pronuclear transfer and spindle transfer, mitochondrial gene replacement raises ethical and social concerns.
Mitochondrial donation involves modification of the germline, and hence such modifications would be passed on to subsequent generations. Using human embryos for in vitro research is also controversial, as embryos are created specifically for research and egg donors are induced to undergo the procedure by financial compensation.
Mitochondrial donation also has the potential for psychological and emotional impacts on an offspring through an effect on the person's sense of identity. Ethicists question whether the genetic make-up of children born as a result of mitochondrial replacement might affect their emotional well-being when they become aware that they are different from other healthy children conceived from two parents.
Opponents argue that scientists are "playing God" and that children with three genetic parents may suffer both psychological and physical damage.
On the other hand, New York University researcher James Grifo, a critic of the American ban, has argued that society "would never have made the advances in treating infertility that we have if these bans had been imposed 10 years" earlier.
On February 3, 2016, the Institute of Medicine of the National Academies of Sciences, Engineering, and Medicine issued a report, commissioned by the U.S. Food and Drug Administration, addressing whether it is ethically permissible for clinical research into mitochondrial replacement techniques (MRT) to continue. The report, titled Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations, analyzes multiple facets of the arguments surrounding MRT and concludes that it is ethically permissible to continue clinical investigations of MRT, so long as certain conditions are met. It recommended that initially the technique should only be used for male embryos to ensure that DNA with potential mitochondrial disease would not be passed on.
In 2018 Carl Zimmer compared the reaction to He Jiankui's human gene editing experiment to the debate over MRT.