In diploid organisms, the frequency and nature of sexual cycles have a major impact on genome-wide patterns of heterozygosity. Recent population genomic surveys in the budding yeast, Saccharomyces cerevisiae, have revealed surprising levels of genomic heterozygosity in what has been traditionally considered a highly inbred organism. I review evidence and hypotheses regarding the generation, maintenance, and evolutionary consequences of genomic heterozygosity in S. cerevisiae. I propose that high levels of heterozygosity in S. cerevisiae, arising from population admixture due to human domestication, coupled with selfing during rare sexual cycles, can facilitate rapid adaptation to novel environments.