<p>Connexin 43 (Cx43) is the most abundant subtypes of the connexin family and is widely expressed across most tissues. It plays a pivotal role in various cellular processes, including development, proliferation, apoptosis, and differentiation. Numerous studies have demonstrated the tumor-suppressive functions of Cx43 in several cancer types. However, some studies have contradicted these findings, showing Cx43 overexpression in certain tumors. These divergent observations suggest that the Cx43 expression and the formation of hemichannels may be context-dependent, varying with cancer type, and exerting different effects on cancer cell behavior in primary versus metastatic sites. In primary tumors, Cx43 can suppress cancer cell proliferation and growth, and promote apoptosis, through both gap junction-dependent or -independent mechanisms. Conversely, in metastatic tumors, Cx43-mediated gap junctions may facilitate direct communication between the metastatic cancer cells and surrounding normal cells, promoting the establishment of metastases. Understanding the signaling pathways that regulate Cx43 function during different stages of tumor development will expand our knowledge about the molecular mechanisms underlying tumor initiation, growth, and metastasis, and may inform the development of novel therapeutic strategies. In this review, we explore the role of Cx43 in regulating signaling pathways involved in cancer cell initiation, growth, and metastasis.</p>