Humans and yeast have domesticated each other. We’ve adapted to living and working together over millennia, and we’ve all changed in the process. Consequently, “natural” or “wild” ferments are never entirely natural or wild. Inoculated ferments aren’t entirely under human control, either. DNA sequencing now makes it possible to identify which yeast strains are involved in a particular fermentation, irrespective of how they came to be there, and to ask: how have the past 150 years of efforts to standardize and commercialize Saccharomyces cerevisiae shaped contemporary wine fermentation landscapes? This chapter reviews recent research into human-microbial co-domestication, the “naturecultural” history of winemaking yeast, yeast diversity across inoculated and non-inoculated wines, and challenges in talking about yeast-human working relationships.