Systemic therapy and spine radiotherapy (RT) can both be important treatments for patients with cancer in the spine. Integration and sequencing of systemic therapies and spine RT depend upon the cancer and the type of systemic therapy. Patients with primary spine cancers undergoing RT in the definitive setting should generally follow treatment protocols appropriate to the cancer in question. This may include concurrent chemotherapy and RT, such as in cases of Ewing sarcoma. In metastatic cancer to the spine, overlap between cytotoxic therapies and spine RT is generally avoided and allowance of sufficient washout is felt to reduce the risk of synergistic toxicity. Targeted therapies are often held for a brief period before and after spine RT. It is usually acceptable to continue immunotherapy during spine RT, with consideration of special circumstances, such as RT overlap with an organ that previously had immunotherapy toxicity. Antibody-drug conjugates can usually be continued, and consideration can be given to administering RT midway between drug cycles. Hormonal therapies can be continued during spine RT.