Genomic instability refers to the tendency of accumulating genomic alterations during cell division. It is a hallmark of cancer and a characteristic feature of most malignant cells. Tumors can develop due to genetic alterations that stimulate cell proliferation or prevent cell death, resulting in the formation of abnormal tissue masses. Many of these genetic alterations affect tumor suppressor (TS) genes. Typically, both alleles of the TS gene must be altered for a phenotypic effect to occur. TS genes can be categorized as “gatekeepers” and “caretakers.” Caretaker genes prevent genomic instability, while gatekeeper genes directly control cell proliferation. Mutation of caretaker genes accelerates the transformation of normal cells into neoplastic cells. Cancer cells employ various strategies to delay DNA repair, such as mutations and epigenetic alterations in repair genes, as well as regulating their expression and functions. They can also disrupt DNA repair through kataegis, chromothripsis, and chromoplexy, which are clustered mutations that overwhelm the repair process. Protective mechanisms like DNA damage checkpoints, DNA repair systems, and the mitotic checkpoint safeguard the integrity of the genome. The DNA damage response, which includes key signaling molecules like ATM, ATR, Chk1, and Chk2, regulates cell cycle progression and addresses DNA damage. Dysfunction in these mechanisms leads to genomic instability and increases the risk of malignant transformation. Both genetic and epigenetic factors contribute to genomic instability, specifically through telomere shortening. This process has been associated with an elevated risk of tumor development due to increased instability. It is crucial to understand these pathways and the interplay between them for cancer progression. Targeting DNA repair genes has shown promise in cancer therapy, but understanding the mechanisms of drug resistance is also important for their effectiveness. This chapter explores the potential of targeting cell cycle checkpoints in new cancer drugs and the molecular mechanisms of genomic instability, with a focus on caretaker genes and their role in tumorigenesis.