Domestication of wild animal and plant species may be considered the largest genetic experiment in human history. Human selection for specific traits and targeted breeding over hundreds or thousands of generations has shaped very special populations that provide unique opportunities for research. Domestic animal genetics contributes to technological advances facilitating a more sustainable, environment- and climate-friendly food production that respects changing societal expectations related to ethical and animal welfare issues. Domestic animal genetics also enables fundamental insights into gene functions and provides animal models for biomedical research. In this collection, curated by Associate Editor Tosso Leeb, we present a selection of PLOS Genetics research that exemplifies recent progress in domestic animal genetics and areas for future development.