Clostridium perfringens ε-toxin (ETX) is the main toxin resulting in enterotoxemia of sheep and goats. ETX can cause lesions of multiple organs, such as hydropericardium, pulmonary edema and focal symmetrical encephalomalcia (FSE). Significant advancements have been made in studies of the cytotoxicity and neurotoxicity of ETX; however, candidates of ETX receptor still remain unconfirmed. Evidence has indicated several candidate molecules to be involved in the recognition and binding of ETX to different target cells. Myelin and lymphocyte (MAL) protein might be one of the candidate receptors for ETX, although this action needs further confirmation. Multiple signaling pathways of cell death are involved in the cytotoxicity of ETX. In Madin-Darby Canine Kidney (MDCK) cells cytotoxicity of ETX was thought to be associated with pore formation, which induces destruction of cellular ion balance. Hemolysis of human erythrocytes induced by ETX required activation of P2 receptors. Therefore, host-related factors are involved in ETX-induced cytotoxicity, which provides potential targets to block the toxic effect of ETX.