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This paper highlights several key issues, ideas, and findings that significantly contribute to our understanding of the organization, communication, and molecular machinery of the liver. The functional anatomy of the liver has been studied in several ways that have revealed the extent of the biliary tree within the hepatic parenchyma, including identification of the canals of Hering as their most distal ramification. The canals of Hering are also considered as the potential residence of hepatic progenitor cells. Hepatocytes can “communicate” with each other via gap junctions, but might also deliver hormones and nucleotides downstream to cholangiocytes. The interaction of inflammatory cells and inflammatory mediators with hepatocytes is of particular importance in transplant immunology, infection, inflammation, viral hepatitis, and fibrogenesis. The role of these mediators as well as certain “toxic” bile acids in apoptosis has become clearer with the discovery of the mitochondrial permeability transition. Moreover, ursodeoxycholic acid can reduce apoptosis by minimizing the mitochondrial permeability transition. Two new nuclear hormone receptors, PXR and SXR, have been identified. These are both activated by a variety of chemically distinct ligands, whose final common goal is the activation of cytochrome P450-containing drug-metabolizing enzymes. Thus, these two receptors are critical to the body’s ability to metabolize a variety of compounds properly. Additional insight into the role of cytokines and cytokine receptors in liver regeneration is presented. Finally, in vivo gene therapy of liver-expressed genes by chimeric oligonucleotides appears quite promising as a means of correcting single nucleotide gene defects.