The muscle-specific helix-loop-helix proteins MyoD and myogenin have been shown to positively autoregulate their own expression and to cross-activate one another's expression following transfection into a variety of nonmyogenic cell lines. We show that the ability of an exogenous myogenin expression vector to activate the endogenous myogenin allele in 10T1/2 fibroblasts is dependent on serum withdrawal. Repression of myogenin autoregulation by serum can be observed with a reporter gene linked to myogenin upstream sequences, indicating that repression occurs at the level of transcription. Like MyoD, myogenin exhibits a short half-life (approximately 20 min), which may serve to maintain the autoregulatory loop without allowing excess accumulation of the protein.