Systems and methods relate to multi-modal imaging of tissue combined with highly focused radiation interventions. The system is a portable multimodal imaging unit that integrates imaging and image analysis. The system can be retrofitted to use with any commercial radiation therapy machine. In one aspect, a system integrates various imaging modalities into a single, coordinated structure. The system integrates X-ray and cone beam computed tomography (CBCT), optical imaging (such as bioluminescent imaging (BLI), fluorescence tomography (FT)), and positron emission tomography (PET) imaging in a single, self-contained structure.