Radiotherapy has traditionally been used as a therapy directed to the primary site of disease to achieve local and regional control. This role is rapidly changing with radiotherapy now playing an integral part of systemic therapy in patients with metastatic disease. Stereotactic body radiotherapy to each oligometastatic site is now actively being evaluated as a means to more definitively control disease and contribute to a longer progression free interval. Irradiation of a tumor site can result in clinically important immuno-modulatory systemic effects which when combined with certain immunotherapy agents can result in abscopal responses at unirradiated sites harboring macroscopic and microscopic disease. Technological advances have now made the delivery of targeted systemic radiotherapy a reality. Systemic radiotherapy can be biologically guided as in the case of radiolabeled peptide analogs or immunologically guided as in the case of radiolabeled antibodies directed against tumor associated antigens. Recent advances in intensity modulated radiation therapy allow for radiation dose sculpting to the entire body resulting in a more targeted form of total body irradiation, also referred to as total marrow irradiation. This targeting is CT image guided to a specific anatomic region, but in the future is expected to incorporate PET and MRI based functional imaging allowing for systemic radiotherapy which is biologically guided based on the unique physiologic, phenotypic and genotypic properties of the tumor. This chapter will summarize the progress, current state and future directions of targeted systemic radiotherapy. The treatment of hematopoietic malignancies is used to illustrate important principles which are applicable to other malignant conditions.