BACKGROUND The interactions of Epidermal Growth Factor Receptor (EGFR) and topoisomerases have been seen in various cancer including brain, breast, ovarian, colorectal, gastric, etc. METHODS The studies in adenocarcinoma patients, chromogenic in situ hybridization, western blotting, receptor binding assay and electromobility shift assays, etc. threw light on the biophysical and biochemical features of EGFR and Topoisomerase cross-talks. RESULTS It has been revealed that both the isomers of topoisomerase (Topo I and Topo II) interact via different mechanisms with EGFR. Topo II and HER2 share the same location i.e. 17q12-21 regions which could be a possible cause of predominant interactions seen between them. Topo I and EGFR interactions are mechanically related to the nucleolar translocation of heparenase by EGF and c-Jun. CONCLUSION We compiled literature findings including the mechanistic interventions, signaling pathways, patents, in vitro and in vivo data of tested inhibitors and combinations in clinical trials, which provide convincing confirmations for the interactions of EGFR and topoisomerases. These interactions may be used for deriving a consistent route of mechanism, design and development of standard drug combinations and dual or multi inhibitors.