DNA damage occurs from both endogenous and exogenous sources and DNA damaging agents are a mainstay in cancer therapeutics. DNA damage sensors (DDS) are proteins that recognize and bind to unique DNA structures that arise from direct DNA damage or replication stress and are the first step in the DNA damage response (DDR). DNA damage sensors are responsible for recruiting transducer proteins that signal downstream DNA repair pathways. As the initiating proteins, DDS are excellent candidates for anti-cancer drug targeting to limit DDR activation. Here, we review four major DDS: PARP1, RPA, Ku, and the MRN complex. We briefly describe the cellular DDS functions before analyzing the structural mechanisms of DNA damage sensing. Lastly, we examine the current state of the field towards inhibiting each DDS for anti-cancer therapeutics and broadly discuss the therapeutic potential for DDS targeting.