Cellular homeostasis in many organs is maintained via gap junctions composed of connexin (Cx), a large protein family with a number of subtypes. In fact, gap junctional intercellular communication (GJIC) is actively involved in all aspects of the cellular life cycle, ranging from cell growth to cell death. It has been well known that Cx genes act as tumor suppressor genes in GJIC-dependent and GJIC-independent manners. Actually, cancers have two different phenotypes on Cx expression and localization in cells; one shows complete silencing of Cx gene, other shows normal expression of Cx gene but disruption of localization of Cx protein. The former has the down-regulation of Cx functions as GJICdependent transformation, and the latter has disruption of Cx localization as GJIC-independent transformation. Thus, in order to restore Cx-dependent functions in cancers and establish the new cancer therapy based on tumor-suppressive effects of Cx gene, we should develop different procedures on each cancer which has the two different phenotypes. In this mini-review, we summarize the tumor-suppressive effects of Cx genes and refer to a possibility of development of a new cancer therapy based on the restoration of the tumor-suppressive effects.