This review focuses on the potential of 1,8-Naphthyridine derivatives in the chemotherapeutic cancer treatment and highlights significant recent progress in the synthetic development of 1,8-naphthyridines as antitumor agents. The present review provide the classical (Skraup, Doebner-Von-Miller, Gould– Jacob, Meth-Cohn, Friedlander, Pfitzinger, Knorr and Conard Limpach, Combes, Niementowski and Pictet-Spengler) and green approaches (metal free ionic liquid mediated reactions, microwave irradiation reactions) for synthesis of 1,8-naphthyridines. 1,8-naphthyridine derivatives which exert their anticancer activity via several mechanisms like apoptosis inducing agents, cell cycle arrest, topoisomerase I and II inhibitors, tubulin polymerization inhibitors, protein kinase inhibitors, intercalation with DNA, angiogenesis inhibitors, Ras protein inhibitors and telomerase inhibitors, are highlighted with proper synthetic methods, SAR studies and molecular docking.