The presence of both cytoplasmic and nuclear genomes within eukaryotic cells raises fascinating questions about co-evolution between genomic compartments that experience fundamentally different mutation rates and modes of inheritance. The highly mutagenic environments found in the mitochondria of some eukaryotes have generated interest in the role that mitochondrial mutation accumulation plays in phenomena such as intracellular gene transfer, compensatory evolution in the nucleus and the evolution of reproductive isolation. Although plant systems have played an important historical role in the study of cytonuclear co-evolution, they remain underutilized in many respects. In particular, the enormous natural variation in DNA substitution rates, gene content and genome architecture in plant mitochondria – much of which has even been found within a single genus – provides opportunities to resolve longstanding evolutionary questions about the consequences of mitochondrial mutation accumulation. This review summarizes some of the classic questions about cytonuclear co-evolution that could be addressed by taking advantage of the variation in plants and highlights a recent analysis of the effect of mitochondrial mutation accumulation on rates of molecular evolution in the nucleus.