The expressions and activities of several CCAAT/enhancer-binding proteins (C/EBP) isoforms fluctuate in the regenerating liver. The physiological implications of these variations in C/EBP function remain poorly characterized in the setting of regeneration. However, lessons learned in various hepatocyte cell lines and by studying primary hepatocytes from transgenic C/EBPalpha-deficient mice suggest that the C/EBP isoforms are likely to influence proliferation, differentiated gene expression, and survival in mature, adult hepatocytes. In addition, these factors are potentially important modulators of liver nonparenchymal cell genes, including those that encode matrix molecules and growth factors that are required for successful liver regeneration. The possibility that members of the C/EBP family of transcription factors actively participate in many aspects of the regenerative response to liver injury is strengthened by growing evidence that many hepatocyte mitogens and co-mitogens regulate C/EBP activity. Furthermore, the C/EBPs themselves appear to regulate the expression of some of these growth regulators.