Hepatic acute phase response is defined as the metabolic reaction of the liver to systemic tissue injury (93). The most prominent change is seen in the pattern of plasma proteins synthesized by the liver (84). The production, and consequently the plasma concentration, of a number of proteins, termed the acute phase reactants, is increased whereas that of some other proteins is reduced (84,94,95). The physiologic significance of the liver reaction is tied to the functions of the regulated plasma proteins (87). The major contributions of acute phase reactants involve neutralizing the harmful consequences of tissue injury such as inhibiting proteases, clearing Superoxide anions, removing freed hemoglobin, and opsonizing particulate matter. Moreover, acute phase reactants contribute to blood clotting, modulate the activity of the immune system, and provide substrates for tissue repair (57,90). The fact that the hepatic acute phase reaction has been evolutionarily conserved in vertebrate species under scores the assumed primary role of this response in controlling systemic homeostasis (93). The biology and physiology of the in vivo hepatic acute phase reaction, the biochemistry of the individual reactants in a variety of vertebrate species, and regulation of acute phase protein synthesis have been subject to a number of excellent reviews (3,46a,50,57,84,86,87,90,96,143) and need not, therefore, be repeated here. In the last few years, major progress has been made toward a) identification of the potential mediators of the liver regulation, b) reproduction of the liver cell reaction in vitro, and c) delineation of the cellular and molecular mechanisms by which the acute phase protein genes are regulated. Moreover, by recognizing that the liver is controlled by systemically acting polypeptide cytokines, studies on hepatic acute phase reaction became interdisci plinarian in nature, involving such fields as immunology, endocrinology, and developmental biology. In view of the increasing concentration on liver cell regulation, this article focuses on the development of in vitro systems that reproduce regulatory properties of the acute phase liver. I will include data from recent experiments with rat hepatoma cells in my laboratory, which should illustrate advantages and disadvantages of a given system. Undoubt edly, considerations similar to the ones presented here will apply to other systems as well.