Cardiac hypertrophy induced by pressure overload and following myocardial infarction entails regulation of myocardial gene expression, recapitulating an embryonic phenotype, including activation of fetal β-myosin heavy chain and skeletal α-actin. Progressive hypertrophy and alterations in gene expression may contribute to myocardial failure. Although signaling pathways that contribute to hypertrophy development have been identified, intrinsic cardiac regulators that limit hypertrophic response have not been determined. The β subunit of S100 protein is induced in the myocardium of human subjects and an experimental rat model following myocardial infarction. Forced S100β expression in neonatal rat cardiac myocyte cultures and high level expression of S100β in transgenic mice hearts inhibit cardiac hypertrophy and the associated phenotype by modulating protein kinase C-dependent pathways. S100β expression is probably a component of the myocyte response to trophic stimulation that serves as a negative feedback mechanism to limit cellular growth and the associated alterations in gene expression. Key words: gene expression, cardiac myocytes, growth factors, heart failure, calcium-binding proteins