Mitochondria are essential cytoplasmic organelles that generate energy (ATP) by 
oxidative phosphorylation and mediate key cellular processes such as apoptosis. 
They are maternally inherited and in humans contain a 16,569-base-pair circular 
genome (mtDNA) encoding 37 genes required for oxidative phosphorylation. 
Mutations in mtDNA cause a range of pathologies, commonly affecting 
energy-demanding tissues such as muscle and brain. Because mitochondrial 
diseases are incurable, attention has focused on limiting the inheritance of 
pathogenic mtDNA by mitochondrial replacement therapy (MRT). MRT aims to avoid 
pathogenic mtDNA transmission between generations by maternal spindle transfer, 
pronuclear transfer or polar body transfer: all involve the transfer of nuclear 
DNA from an egg or zygote containing defective mitochondria to a corresponding 
egg or zygote with normal mitochondria. Here we review recent developments in 
animal and human models of MRT and the underlying biology. These have led to 
potential clinical applications; we identify challenges to their technical 
refinement.