Cancer therapeutics include an ever-increasing array of tools at the disposal of clinicians in their treatment of this disease. However, cancer is a tough opponent in this battle and current treatments which typically include radiotherapy, chemotherapy and surgery are not often enough to rid the patient of his or her cancer. Cancer cells can become resistant to the treatments directed at them and overcoming this drug resistance is an important research focus. Additionally, increasing discussion and research is centering on targeted and individualized therapy. While a number of approaches have undergone intensive and close scrutiny as potential approaches to treat and kill cancer (signaling pathways, multidrug resistance, cell cycle checkpoints, anti-angiogenesis, etc.), much less work has focused on blocking the ability of a cancer cell to recognize and repair the damaged DNA which primarily results from the front line cancer treatments; chemotherapy and radiation. More recent studies on a number of DNA repair targets have produced proof-of-concept results showing that selective targeting of these DNA repair enzymes has the potential to enhance and augment the currently used chemotherapeutic agents and radiation as well as overcoming drug resistance. Some of the targets identified result in the development of effective single-agent anti-tumor molecules. While it is inherently convoluted to think that inhibiting DNA repair processes would be a likely approach to kill cancer cells, careful identification of specific DNA repair proteins is increasingly appearing to be a viable approach in the cancer therapeutic cache.