The loss of homeostasis which characterizes tumor growth is probably the result of a deregulated intercellular communication capacity of the cancer cells. The deregulation of gap-junctional intercellular communication (GJIC) was observed in in vivo and in vitro carcinogenesis models. Our studies using gap-junction protein (connexin) molecular probes indicate that the loss of GJIC during carcinogenesis and in tumors involves aberrations at multiple levels of regulatory mechanisms of connexins. Tumor promoters, such as phorbol esters and phenobarbital, are known to inhibit GJIC. Our recent work with mouse epidermal cells suggests that TPA inhibits GJIC without af-fecting the amount of Cx43 mRNA, but that it acts at a post-translational level. This is in contrast to our previous in vivo observation that the liver-tumor promoter, pheno-barbital, decreases Cx32 mRNA level in the rat liver. These results suggest that different types of tumor pro—moters inhibit GJIC at different regulatory levels. Similarly, analysis of GJIC and connexin expression of cells at different stages of carcinogenesis suggests multi-ple mechanisms of GJIC deregulation. For example, we found a progressive decrease of GJIC in a series of rat liver epithelial cell lines and mouse epidermal cell lines which paralleled the progressively malignant phenotypes. However, the level of Cx43 gene expression was similar in each series of cell lines. On the other hand, GJIC loss in primary pre-neoplastic foci and tumors induced in rat liver was associated with a decreased level of Cx32 mRNA and protein, as measured by immunostaining. In