The pathogenesis of chronic Chagas cardiomyopathy (CCC) is still being unraveled. In the last decade, a role for inflammatory cytokines on tissue damage has been shown. The present review will address the molecular and immunological mechanisms of tissue damage on human CCC with a special focus on results obtained by our research group using genomic and proteomic approaches. The results suggest that direct modulation of myocardium gene and protein expression by inflammatory cytokines may be a new pathogenic mechanism in CCC, with therapeutic implications.