The invention and approval of innovative anticancer therapies in the last decade have revolutionized oncology treatment. Radiotherapy is one of the three traditional pillars in oncology treatment with surgery and systemic therapies. Some standard-of-care combinations of chemoradiotherapy widened the therapeutic window of radiation, while some other chemotherapies such as gemcitabine caused unacceptable toxicities when combined with radiation in lung cancers. Fast-paced progress are specially focused on immunotherapies, targeted-therapies, anti-angiogenic treatment, DNA repair inhibitors, hormonotherapy and cell cycle inhibitors. New anticancer therapeutic arsenals provided new possibilities of combined oncological treatments. The interactions of the radiotherapy with other systemic treatments, such as non-anticancer immunomodulatory/immunosuppressive medications are sometimes overlooked even though they could offer a real therapeutic benefit. In this review, we summarize the new opportunities and the risks of historical and novel combined therapies with radiation: non-anticancer immunomodulatory/immunosuppressive drugs, systemic reoxygenation, new therapies such as nanoparticles and SMAC mimetics. Key biological mechanisms, pre-clinical and available clinical data will be provided to demonstrate the promising opportunities in the years to come.