DNA damage plays a causal role in numerous disease processes. Hence, it is suggested that DNA repair proteins, which maintain the integrity of the nuclear and mitochondrial genomes, play a critical role in reducing the onset of multiple diseases, including cancer, diabetes and neurodegeneration. As the primary DNA polymerase involved in base excision repair, DNA polymerase ß (Polß) has been implicated in multiple cellular processes, including genome maintenance and telomere processing and is suggested to play a role in oncogenic transformation, cell viability following stress and the cellular response to radiation, chemotherapy and environmental genotoxicants. Therefore, Polß inhibitors may prove to be effective in cancer treatment. However, Polß has a complex and highly regulated role in DNA metabolism. This complicates the development of effective Polß-specific inhibitors useful for improving chemotherapy and radiation response without impacting normal cellular function. With multiple enzymatic activities, numerous binding partners and complex modes of regulation from post-translational modifications, there are many opportunities for Polß inhibition that have yet to be resolved. To shed light on the varying possibilities and approaches of targeting Polß for potential therapeutic intervention, we summarize the reported small molecule inhibitors of Polß and discuss the genetic, biochemical and chemical studies that implicate additional options for Polß inhibition. Further, we offer suggestions on possible inhibitor combinatorial approaches and the potential for tumor specificity for Polß-inhibitors.