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The Clostridium perfringens epidemic threatens biosecurity and causes significant economic losses. C. perfringens infections are linked to more than one hundred million cases of food poisoning annually, and 8–60% of susceptible animals are vulnerable to infection, resulting in an economic loss of more than 6 hundred million USD. The enzymes and toxins (>20 species) produced by C. perfringens play a role in intestinal colonization, immunological evasion, intestinal micro-ecosystem imbalance, and intestinal mucosal disruption, all influencing host health. In recent decades, there has been an increase in drug resistance in C. perfringens due to antibiotic misuse and bacterial evolution. At the same time, traditional control interventions have proven ineffective, highlighting the urgent need to develop and implement new strategies and approaches to improve intervention targeting. Therefore, an in-depth understanding of the spatial and temporal evolutionary characteristics, transmission routes, colonization dynamics, and pathogenic mechanisms of C. perfringens will aid in the development of optimal therapeutic strategies and vaccines for C. perfringens management. Here, we review the global epidemiology of C. perfringens, as well as the molecular features and roles of various virulence factors in C. perfringens pathogenicity. In addition, we emphasize measures to prevent and control this zoonotic disease to reduce the transmission and infection of C. perfringens. [ABSTRACT FROM AUTHOR]