Partial hepatectomy and toxic liver damage induce signals in the liver that result in rapid changes in the transcriptional milieu, including activation of latent transcription factors NF-kappa B and STAT3, and induction of expression of early growth response genes. Several of these changes within hepatocytes, including STAT3 and NF-kappa B induction are dependent on the cytokines, TNF alpha and interleukin-6 (IL-6), that are presumably released from non-parenchymal liver cells within minutes of the hepatectomy. IL-6 is a critical factor in the mitogenic response during liver regeneration and is important for both cell cycle progression and protection from liver injury. However, it is not a complete factor in that it is responsible for only a subset of the gene expression changes that occur after hepatectomy and is insufficient alone to cause hepatic DNA synthesis. C/EBP beta, a leucine zipper transcription factor, acts in an IL-6 independent fashion to induce a separate set of genes and proteins and is also required for normal liver regeneration. Moreover, some early growth response genes such as PRL-1, which encodes a nuclear protein tyrosine phosphatase, are induced normally in the absence of C/EBP beta and IL-6 and highlight the role of other transcriptional complexes such as Egr-1 in the early phases of liver regeneration. Thus, cytokine-dependent and -independent pathways act cooperatively to control the complex series of events that result in liver regeneration. The requirement for multiple signals also protects the liver from undergoing hyperplasia in the absence of a compensatory need.