Enteroviruses of the Picornaviridae and primarily coxsackieviruses of group B (CVB) can be detected in humans and various experimental murine models of acute myocarditis and chronic heart muscle diseases indicating enterovirus persistence in the myocardium. Persistent myocardial infection is characterized by restricted viral replication and gene expression in myocytes capable of sustaining chronic inflammation. Viral cytotoxicity was found to be crucial for organ pathology both during acute and persistent infection. In-situ hybridization experiments at the cellular and subcellular level have demonstrated that virus replication is associated with severe structural changes of the cardiomyocyte cytoarchitecture at any stage of the disease. In tissue culture experiments and transgenic mice, it was shown that restricted replication and gene expression of the virus are capable of inducing myocytopathic effects. Investigations at the molecular level revealed that interference of coxsackievirus replication with the cellular metabolism is mediated by cleavage of host cell proteins by virus-encoded proteinases. Notably, there is also evidence that enteroviruses are able to activate specific cellular signal transduction pathways in the course of infection, thus promoting enteroviral replication. In summary, these data indicate that mutual influences of virus replication and subsequent modifications of the host cell metabolism are crucial for cardiac injury and dysfunction during acute and chronic disease.