This review examines the immunologic rationale for immunosuppressive and immunomodulating therapy. The controversy as to whether immunosuppressive treatment is beneficial in myocarditis will continue even after the Myocarditis Treatment Trial, which demonstrated that in active myocarditis identified by the Dallas criteria but without taking into account presence or persistence of viral RNA or DNA or signs of autoreactivity, immunosuppression did not influence either central hemodynamics or prognosis significantly. These findings concur in part with data from experimental mice and also with sporadic human data. In the acute stage of inflammatory viral heart disease, immunosuppressive drugs should be avoided. This recommendation can be upheld even in the light of the Myocarditis Treatment Trial. It is still unresolved, however, whether this also applies in chronic myocarditis with (enteroviral) persistence, in which the residual viral genome may have been rendered noninfective, making it the equivalent of a “scar” or “tombstone” of former infection. Here, demonstration of the viral genome in does not necessarily imply actively replicating virus. Furthermore, evidence is accumulating that the formerly reported incidence of enteroviral persistence in endomyocardial biopsies may have been overestimated. In autoreactive forms of myocarditis with documented humoral and cellular effector mechanisms, studies indicate that immunosuppressive treatment may be useful. However, data from the double-blind, randomized European Study of the Epidemiology and Treatment of Cardiac Inflammatory Disease must be awaited before conclusions can be made. We therefore recommend enrolling virus-negative patients in randomized, controlled treatment trials to validate the benefit of these treatment regimens. In addition, hyperimmunoglobulin therapy appears to be of particular interest because it has shown few side effects but has positive results in cytomegalovirus-associated myopericarditis in humans.