Without mitochondria we would be in big trouble, and there would be a global biological energy crisis if it were not for chloroplasts. Fortunately, genomic evolution over the past two billion years has ensured that the functions of these key organelles are with us to stay. Whole-genome analyses have not only proven that mitochondria and chloroplasts are descended from formerly free-living bacteria, but have also shown that it is difficult to define eukaryotes without reference to the fusion and coevolution of host and endosymbiont genomes. Here, we review how the macro- and microevolutionary insights that follow from the genomics of cytonuclear interactions are uniting molecular evolution, structural proteomics, population genetics and problems in aging and disease. Our goals are to clarify the coevolutionary events that have governed nuclear and organelle evolution, and to encourage further critical analyses of these interactions as problems in the study of co-adapted gene complexes.