We have developed a cell culture system to study molecular mechanisms important in myocardial hypertrophy. α₁-Adrenergic receptor stimulation produces hypertrophy of neonatal rat cardiac myocytes. Myocyte hyperplasia is not induced by α₁ stimulation, although α₁-adrenergic receptor-mediated DNA synthesis and cell division have been observed in other types of cells. The myocyte hypertrophic response does not require contractile activity. Activation of the α₁ receptor also produces highly specific alterations in gene expression, as measured at the mRNA and protein levels. In particular, there is selective up-regulation of two contractile protein isogenes that are expressed in vivo during early development and in pressure-load hypertrophy, skeletal α-actin and β-myosin heavy chain. Studies with an in vitro transcription assay indicate that stimulation of the α₁-adrenergic receptor leads to a distinctive temporal sequence of transcriptional activation. Transcription of the skeletal α-actin isogene is induced preferentially to that of cardiac α-actin. Thus, early developmental isogene induction in α₁-stimulated hypertrophy reflects a fundamental change in the transcriptional program of the cardiac myocyte nucleus. The goal now is to define an intracellular pathway connecting the α₁-adrenergic receptor in the plasma membrane to activation of RNA polymerase II on the skeletal α-actin gene in the cardiac myocyte nucleus. There is evidence that protein kinase C may be one component of this pathway. A model for α₁-mediated transcription is presented.