<p>Porcine epidemic diarrhea virus (PEDV) is an enteric alphacoronavirus that has shifted from a sporadic regional pathogen to a worldwide, persistent virus, despite years of vaccination, biosecurity measures, and monitoring. Since the early 1970s, PEDV has shown strong genetic flexibility, the ability to evade immunity, survive in the environment, and spread quickly through connected livestock networks. Major outbreaks in Asia, Europe, and North America, especially the 2013–2014 outbreak in the United States, have revealed key weaknesses in traditional control methods for enteric coronaviruses, especially those that depend on systemic immunization. In this review, we bring together over fifty years of PEDV research to look at how viral evolution, mucosal immune responses, and livestock production systems work together to keep the virus circulating. We point out that changes in the spike gene, including recombination and deletions, along with changes in other viral genes, affect disease severity, immune system recognition of the virus, and the inability of vaccines to provide protection. We also stress the key role of lactogenic immunity and the gut-mammary-secretory IgA system in protecting newborn animals, which helps explain why vaccine inoculations have not been effective in stopping the spread of enteric coronaviruses. By combining evidence from molecular, immune, epidemiological, and systems research, we suggest that PEDV is a strong example for studying how coronaviruses persist under immune pressure in managed animal groups. Using a One Health approach, this review encourages moving away from only reacting to outbreaks and instead focusing on ongoing, genome-based management of coronaviruses in livestock operations.</p>