The expression of cellular myc (c-myc) was studied during early and late stages of chemical hepatocarcinogenesis in the rat using Northern blot analysis and in situ hybridization. Hepatocarcinogenesis was induced according to the resistant hepatocyte model of Solt and Farber. An uninitiated version of this model was also used to examine the expression of c-myc during proliferation and differentiation of oval cells. The expression of c-myc was increased throughout hepatocarcinogenesis starting with early preneoplastic foci and oval cells. Similar levels of c-myc transcripts were detected in oval cells and basophilic hepatocytes generated by the uninitiated version of the protocol as were found in preneoplastic foci and oval cells during hepatocarcinogenesis. Whereas c-myc expression remained elevated in late neoplastic nodules and carcinomas, it gradually declined in both "remodelling" nodules and uninitiated livers. Our data indicate that c-myc expression is elevated during the undifferentiated stages of hepatocyte development. Furthermore, the data support the hypothesis that a critical early step in chemical hepatocarcinogenesis involves a block in the normal differentiation program of the hepatocytes.