The most challenging problem in speciation research is disentangling the relative strength and order in which different reproductive barriers evolve. Here, we review recent developments in the study of reproductive isolation in yeasts. With over a thousand genome-sequenced isolates readily available for testing the viability, sterility, and fitness of both intraspecies and interspecies hybrid crosses,Saccharomycesyeasts are an ideal model to study such fundamental questions. Our survey demonstrates that, while chromosomal-level mutations are widespread at the intraspecific level, anti-recombination-driven chromosome missegregation is the primary reproductive barrier between species. Finally, despite their strength, all of these postzygotic barriers can be resolved through the asexual life history of hybrids.