Coxsackieviruses have been implicated in the pathogenesis of human myocarditis and some forms of dilated cardiomyopathy. A considerable portion of our knowledge about the pathophysiology of viral heart disease is derived from animal studies. In particular, investigations utilising gene-targeted mice provide valuable new insights into various aspects of viral pathogenicity and host factors involved in the control of viral replication. This review focuses on models in cell culture and transgenic animals mimicking coxsackieviral persistence, demonstrating that remarkably low persisting levels of replication-restricted coxsackieviral genomes are associated with an induction of a cytopathic effect in cardiac myocytes, leading to dilated cardiomyopathy in a transgenic mouse model. In this particular animal model, a phenotype is revealed which closely resembles the major hallmarks of human dilated cardiomyopathy. The impact of the innate immune system on coxsackieviral replication is demonstrated by studies in gene-targeted mice deficient of either type I or type II interferon signalling, which have indicated that type I but not type II interferons are essential for the control of early viral replication and survival of coxsackieviral infection.