Sterile tissue injury or infection initiates a local inflammatory response that mobilizes a systemic acute phase reaction resulting in, among other things, the induction of genes encoding the acute phase plasma proteins (APPs). In all vertebrates, a common set of APPs is increased and exerts essential protective functions. Haptoglobin (HP), one of the major APPs, acts as a high-affinity hemoglobin-binding protein and antioxidant. Liver is the major site of HP synthesis; however, regulated, low level expression is also detected in other organs. Induction of the Hp gene is mediated by interleukin-6-type cytokines and is synergistically enhanced by glucocorticoids. Growth stimulation of hepatic cells in vivo or in vitro suppresses the Hp gene-inducing effects of inflammatory cytokines. Receptors for IL-6 cytokines mediate induction of the Hp gene by the transcription factors signal transducer and activator of transcription-3 (STAT3) and CAAT/enhancer binding protein beta (C/EBPbeta), but attenuate the stimulation through co-activated STAT5 and mitogen-activated protein kinases, ERK-1 and ERK-2. The specificity by which the related cytokines, IL-6, oncostatin M, and leukemia inhibitory factor, regulate Hp gene transcription is determined by the profile of the cytokine receptor subunits expressed on the target cells and the relative extents by which these receptors activate the intracellular signaling pathways. The current hypothesis is that HP exerts an anti-inflammatory activity and that by the degree with which HP attenuates the inflammatory process, including the production of IL-6 cytokines, it determines the level and duration of acute phase expression of the Hp gene.