Normal adult liver is uniquely capable of renewal and repair after injury. Whether this response represents simple hyperplasia of various liver elements or requires recapitulation of the genetic program of the developing liver is not known. To study these possibilities, we examined transcriptional programs of adult liver after partial hepatectomy and contrasted these with developing embryonic liver. Principal component analysis demonstrated that the time series of gene expression during liver regeneration does not segregate according to developmental transcription patterns. Gene ontology analysis revealed that liver restoration after hepatectomy and liver development differ dramatically with regard to transcription factors and chromatin structure modification. In contrast, the tissues are similar with regard to proliferation-associated genes. Consistent with these findings, real-time polymerase chain reaction showed transcription factors known to be important in liver development are not induced during liver regeneration. These three lines of evidence suggest that at a transcriptional level restoration of liver mass after injury is best described as hepatocyte hyperplasia and not true regeneration. We speculate this novel pattern of gene expression may underlie the unique capacity of the liver to repair itself after injury.