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Cytolysins inflict cell damage by forming pores in the plasma membrane. The Na+ conductivity of these pores results in an ion influx that exceeds the capacity of the Na+/K+-pump to extrude Na+. This net load of intracellular osmolytes results in swelling and eventual lysis of the attacked cell. Many nucleated cells have the capacity to reduce the potential damage of pore-forming proteins, whereas erythrocytes have been regarded as essentially defenceless against cytolysin-induced cell damage. This review addresses how autocrine/paracrine signalling and the cells intrinsic volume regulation markedly influence the fate of the cell after membrane insertion of cytolysins. Moreover, it regards the various steps that may explain the relative large degree of diversity between cell types and species as well as highlights some of the current gaps in the mechanistic understanding of cytolysin-induced cell injury.