Radiation therapy (RT) remains a mainstay of current clinical management of breast cancer. Although effective in most women, a significant percentage will develop recurrent disease despite this multi-modality therapy, including a significant percentage of the 72,000 women diagnosed with triple-negative breast cancer (TNBC) each year. Studies detailing the poor response of TNBC to adjuvant RT underscore the biologic differences and as yet undefined oncogenic drivers of these particular types of tumors, with TNBC much less likely to have significant disease and metastasis-free survival advantages from adjuvant RT and chemotherapy treatment in women. Given the lack of targeted agents for TNBC and their relative RT insensitivity (as evidenced by their increased locoregional recurrence risk) it is clear that the development of additional targets for radiosensitization and metastasis prevention represents a critical unmet clinical need. We hypothesize that abnormal expression of the kinases and phosphatases modulates the effectiveness of current therapies for triple-negative breast cancer. Additionally, we hypothesize that these proteins are responsible for the radioresistance phenotype found in many ER- and triple-negative breast cancer patients. Understanding the relationship and regulation of these proteins through bioinformatics and wet lab techniques will allow for the development of novel therapies for ER- breast cancer and/or enhanced radiosensitivity, leading to better patient outcomes in the future.