Coxsackieviruses (CV) are characterized by their ability to cause cytopathic effects in tissue culture and by their capacity to initiate acute disease by inducing apoptosis within targeted organs in vivo. These viruses are considered highly cytolytic, but can establish persistence/latency in susceptible cells, indicating that a regulatory mechanism may exist to shut off viral protein synthesis and replication under certain situations. The persistence of coxsackieviral RNA is of particular medical interest due to its association with chronic human diseases such as dilated cardiomyopathy and chronic inflammatory myopathy. Here, we discuss the potential mechanisms regulating coxsackievirus replication, and the ability of viral RNA to remain in an apparent latent state within quiescent cells.