Direct communication between hepatocytes, mediated by gap junctions, constitutes a major regulatory platform in the control of liver homeostasis, ranging from hepatocellular proliferation to hepatocyte cell death. Inherent to this pivotal task, gap junction functionality is frequently disrupted upon impairment of the homeostatic balance, as occurs during liver toxicity and carcinogenicity. In the present paper, the deleterious effects of a number of chemical and biological toxic compounds on hepatic gap junctions are discussed, including environmental pollutants, biological toxins, organic solvents, pesticides, pharmaceuticals, peroxides, metals and phthalates. Particular attention is paid to the molecular mechanisms that underlie the abrogation of gap junction functionality. Since hepatic gap junctions are specifically targeted by tumor promoters and epigenetic carcinogens, both in vivo and in vitro, inhibition of gap junction functionality is considered as a suitable indicator for the detection of nongenotoxic hepatocarcinogenicity.