A radiation therapy system is equipped with a combined imaging system, such as an imaging system combining computed tomography (CT), spectral CT, and single photon emission tomography imaging (SPECT), for guidance of radiation beams providing radiotherapy. The system can include at least one x-ray source that emits an x-ray beam at a low energy level for imaging and/or an x-ray beam at a high energy level for radiation therapy. The system can also include at least one imager, such as a cadmium zinc telluride (CZT) or cadmium telluride (CdTe) flat-panel imager that receives x-ray beams traversing a subject from the x-ray source and gamma rays emitted by radioisotope tracers injected into the subject. Based on the guidance of the triple images (CT, spectral CT, and SPECT), a computer system can control the radiation therapeutic beam delivery to target areas, such as lesions and/or tumors.