The emergence of barriers to reproduction between two populations is one of the most important features of speciation. Among the mechanisms of reproductive isolation are incompatible interactions between gene products of the parental species that reduce the fitness of hybrid individuals. The accumulation of such incompatibilities is described by the Bateson–Dobzhansky–Muller model (BDM)  that provides a framework for understanding how genes can coevolve to stay compatible within populations and become incompatible between populations. Only a handful of such loci have been identified and characterized at the molecular level. In this issue of EMBO Reports, Jhuang and colleagues  show that BDM incompatibilities have accumulated between a nuclear-encoded gene and a mitochondrial ribosomal RNA between two yeast species.