Eukaryotic chromosomal DNA replication is preceded by replication licensing which involves the identification of the origin of replication by origin recognition complex (ORC). The ORC loads pre-replication complexes (pre-RCs) through a series of tightly regulated mechanisms where the ORC interacts with Cdc6 to recruit cdt1-MCM2-7 complexes to the origin of replication. In eukaryotes, adherence to regulatory mechanisms of the replication program is required to ensure that all daughter cells carry the exact copy of genetic material as the parent cell. Failure of which leads to the development of genome instability syndromes like cancer, diabetes, etc. In an event of such occurrence, preventing cells from carrying the defaulted genetic material and passing it to other cells hinges on the regulation of chromosomal DNA replication. Thus, understanding the mechanisms underpinning chromosomal DNA replication and particularly replication licensing can expose druggable enzymes, effector molecules, and secondary messengers that can be targeted for diagnosis and therapeutic purposes. Effectively drugging these molecular markers to reprogram pre-replication events can be used to control the fate of chromosomal DNA replication for the treatment of genome instability disorders and in this case, cancer. This review discusses available knowledge of replication licensing in the contest of molecular drug discovery for the treatment of cancer.