This chapter offers an integrative examination of the historical, genetic, and sociocultural dimensions shaping donkey conservation and breeding worldwide. It begins by tracing the domestication and global dispersal of donkeys from their African wild ass ancestors during the mid-Holocene to their contemporary roles across diverse ecological and cultural landscapes. The historical narrative highlights donkeys’ centrality to trade, agriculture, and colonization, their subsequent decline under industrialization, and recent pressures driven by global demand for donkey-derived products. The second section addresses genetic challenges, including high coancestry, inbreeding, and the erosion of purebred lineages, alongside opportunities for sustainable genetic management. Topics such as incomplete pedigrees, introgression, feral population undervaluation, long generation intervals, and assisted reproduction inefficiencies underscore the complexity of maintaining genetic diversity. Special attention is given to the ambiguous contributions of wild ass populations to modern breeds and the implications of selective breeding for health and adaptability. Finally, the chapter explores anthropological and sociocultural factors influencing donkey populations, including owner-driven inbreeding practices, foreign breed introgression, shifting breed standards, and paradoxical conservation outcomes—endangered in native regions yet invasive abroad. It also discusses economic, cultural, and ethical contexts shaping conservation policies and breeding practices. By integrating archaeological evidence, genetic insights, and sociocultural analysis, the chapter underscores the urgent need for multidimensional strategies combining scientific tools, policy frameworks, and community engagement to secure the future of donkey genetic resources.