In mammals, growth of the fetal heart is regulated by proliferation of cardiac muscle cells. At later stages of pre-natal life, this proliferation diminishes profoundly [1,2] and the dramatic expansion in heart size during the transition to adulthood is due exclusively to hypertrophy of individual cardiomyocytes [3–5]. Cardiomyocyte hypertrophy also contributes to the pathology of most post-natal heart disease [6–10]. Within this context, numerous signal transduction pathways have been implicated as the link between the effector(s) and altered cardiac gene expression [11–16]. A common pathway has yet to be discovered, however. Here, we found that the activity of the stress-activated kinase p38 was enhanced in both types of cardiomyocyte hypertrophy. We also found that a target of the activated p38 kinase is the cardiac transcription factor MEF2. Transgenic mice expressing a dominant-negative form of MEF2C displayed attenuated post-natal growth of the myocardium. These results provide the first evidence for a single pathway regulating both normal and pathologic cardiomyocyte hypertrophy.