Although rheumatic fever has virtually disappeared in many developed countries, it remains the number one acquired heart disease among children in developing countries. Many hypotheses advanced to explain the pathogenic mechanisms of this disease include the concept of an abnormal humoral and cellular response within the host to streptococcal antigens cross-reacting with mammalian tissues. This report examines the most recent evidence supporting this concept. It emphasizes the importance of the cellular arm of the immune response in cardiac damage, as wall as possible genetic disposition to the disease.