Gap junction is a necessary channel structure composed of connexin proteins, which can form direct communication to exchange material and information between mammal cells. Connexin 43(Cx43)is the most abundant connexin protein expressed in the central nervous system. There is emerging evidence that Cx43 has a wide regulatory effect on the occurrence and development of glioma and play an important role in malignant biological behaviors of glioma. Temozolomide is a currently first-line chemotherapeutic drug for glioma. However, with the prolong of treatment period, the therapy effect of temozolomide is attenuated in some patients because of drug resistance. And the abnormal expression of Cx43 in glioma may be one of the important reasons for temozolomide resistance. In this review, we summarized the structure and function of Cx43, several mechanism of temozolomide resistance and the research progress of Cx43-mediated temozolomide resistance, as well as anti-tumor compounds targeting Cx43 in recent years, in order to provide new evidence for glioma therapy.