Liver regeneration after surgical partial hepatectomy (PH) in animals exposed to the mito-inhibitory agent retrorsine is completed through the outgrowth and expansion of small hepatocyte-like progenitor cells (SHPCs). Although the SHPC-mediated regenerative response has been well characterized in the retrorsine/PH model of liver injury, the role that these cells play in other forms of liver injury has not been investigated. The experimental objectives of the current studies were: (i) to characterize SHPC responses in hepatotoxic and necrotic models of liver injury, (ii) to determine the progenitor cell of origin of SHPCs, and (iii) to identify factors involved in the activation of SHPCs after liver injury. SHPCs are not observed after PH in retrorsine-exposed rats treated with the mito-inhibitory agent 2-acetamidofluorene, but are observed after PH in retrorsine-exposed rats treated with the biliary toxin 4,4'-diaminodiphenylmethane. Together, these observations suggest strongly that oval cells do not represent progenitor cells of SHPCs, but that SHPCs represent another liver progenitor cell population that resides in the hepatic parenchyma and responds to certain forms of liver injury. In addition, these investigations found that SHPCs respond to restore liver mass and structure when retrorsine-exposed rats are treated with the pericentral necrotizing agent carbon tetrachloride. This observation shows that SHPCs are capable of regenerating liver damaged by surgical resection as well as chemically-induced necrotic injury. Finally, these studies establish that treatment of retrorsine-exposed rats with the cytokine inhibitor dexamethasone blocks SHPC proliferation after PH and that this blockade can be overcome by administration of recombinant IL6 protein. These observations suggest that SHPCs are activated for proliferation in a cytokine-dependent manner similar to other regenerative cell populations in liver (mature hepatocytes, oval cells), and that IL6 may function as the master regulatory molecule for activation of progenitor cell responses after liver injury. Together, these investigations provide evidence that a hierarchy of cellular responses exists in the mammalian liver in which the form of regenerative response occurring after liver injury reflects (i) the type of liver injury, and (ii) the progenitor cell populations that are capable of proliferating.