Cancer cells often have downregulated levels of connexins, resulting in reduced levels or loss of intercellular communication via gap junctions. Downregulation of connexins in cancer cells involves multiple mechanisms, including reduced gene transcription, reduced messenger RNA stability or translation, and dysregulation of connexins at the post-translational level. Cancer cells that express connexins at the protein level are often unable to form functional gap junctions because of aberrant regulation of the intracellular trafficking of connexins, resulting in localization of connexins in various cytoplasmic compartments rather than at the plasma membrane. Moreover, many growth factors, oncogenes, and tumor-promoting chemicals induce endocytosis and degradation of connexins. Research by us and others has identified a central role of the ubiquitin system in controlling the level of functional gap junctions at the plasma membrane under basal conditions, in response to exposure to growth factors or tumor promoters, and in response to oxidative stress. An important aim of our current research is to identify the E3 ubiquitin ligases involved in regulating gap junctions levels under normal conditions, and to elucidate whether aberrant regulation of these processes may contribute to the loss of intercellular communication via gap junctions during cancer pathogenesis.