Cancer is one of the leading chronic diseases with a high mortality rate worldwide. Current statistical studies on cancer estimates from the World Health Organization (WHO) in 2020, cancer is the first or second leading cause of death. Although cancer remains a devastating diagnosis, several decades of preclinical progress in cancer biology and biotechnology have recently led to the successful development of several biological agents that substantially improve survival and quality of life for some patients. For over half a century, the carbazole skeleton has been the key structural motif of many biologically active compounds including natural and synthetic products. Carbazoles have taken an important part in all the existing anti-cancer drugs because of their discovery in a large variety of organisms, including bacteria, fungi, plants, and animals. Several natural or synthetic polycyclic molecules with carbazolic nuclei, which show attractive anticancer properties were approved, and their biological activities and their specificity, obtaining cytotoxic agents effective in a panel of various cancer cell lines. The most described carbazole anti-tumor agents were classified according to their structure, starting from the tricyclic–carbazole motif to fused tetra-, penta-, hexa- and heptacyclic carbazoles. This review also highlights the key advancements of Carbazole and its derivatives for cancer therapy and exploration of emerging directions in clinical development that have the potential to impact clinical care in the future in search of cancer therapy.