Enteroviral infection of the heart has been noted in a significant proportion of cases of myocarditis and dilated cardiomyopathy. The presence of enterovirus RNA at stages of disease after acute infection and correlation of enterovirus replication with worse clinical outcome suggests continued replication of the virus is involved in the progression of the disease. This finding is mirrored by the murine model of coxsackievirus B3 myocarditis, in which virus persists through the evolution of the virus to a terminally deleted defective form which persists in the myocardium. Studies of the mechanism of induction of myocarditis by coxsackievirus B3 require assessment of the effects of alterations of the immune response upon virus persistence in this form. As expression of viral proteins in the heart have been shown to generate significant impairment of cardiomyocyte function and promote generation of dilated cardiomyopathy, the role of virus persistence is likely to include direct effects of viral replication as well as induction of inflammation in the heart. Factors that control the extent of cardiac infection with terminally deleted enteroviruses and the relative roles of continued immune response of the virus vs viral modification of cardiac function need to be measured to find effective therapies for the human disease.