Group B coxsackieviruses are members of the picornavirus family of small nonenveloped RNA viruses and have been associated with diseases of multiple organs including the heart, acinar and islet pancreas, liver, skeletal muscle, central nervous system, and testes. Damage to tissues occurs not only from the direct virus replication and infection of cells, but also from the host response to infection. However, without host immunity and response, the viruses are not appropriately cleared and chronic infection occurs. The host response to coxsackieviruses is diverse and complex. Also, the host response both benefits and is detrimental to the virus. This review discusses the major aspects of the host response to coxsackieviruses and attempts to demonstrate the interplay between the virus and the cell, which ultimately determines both the type and strength of the adaptive immune response as well as whether autoimmunity will follow the infection.