AbstractTherapy resistance is imposing a daunting challenge on effective clinical management of breast cancer. Although the development of resistance to drugs is multifaceted, reprogramming of energy metabolism pathways is emerging as a central but heterogenous regulator of this therapeutic challenge. Metabolic heterogeneity in cancer cells is intricately associated with alterations of different signaling networks and activation of DNA damage response pathways. Here we consider how the dynamic metabolic milieu of cancer cells regulates their DNA damage repair ability to ultimately contribute to development of therapy resistance. Diverse epigenetic regulators are crucial in remodeling the metabolic landscape of cancer. This epigenetic–metabolic interplay profoundly affects genomic stability of the cancer cells as well as their resistance to genotoxic therapies. These observations identify defining mechanisms of cancer epigenetics–metabolism–DNA repair axis that can be critical for devising novel, targeted therapeutic approaches that could sensitize cancer cells to conventional treatment strategies.