Doubts about the relevance of mitochondrial mutations for aging and disease usually concentrate on their low frequency found in some studies. Recently, an enormous mutation burden (microheteroplasmy) was discovered with more sensitive detection methods. In the aged adult the vast majority (more than 99%) of mitochondrial genomes are mutated. The biochemical pathways linking them to the aging phenotype are increasingly being elucidated as well. This effort will be aided by the recently developed method for introduction of full-length mitochondrial genomes in vitro and in vivo, protofection. Protofection is independent of the TIM/TOM import machinery and uses a pathway involved in the import of macromolecular complexes. Protofection enables the full replacement of mitochondrial genomes in cells using a restriction-enzyme strategy, with important implications for future therapeutics. We believe that the next decade will be the decade of the mitochondria.