Image-guided small animal radiation research platforms allow more precise radiation treatment. Commercially available small animal X-ray irradiators are often equipped with a CT/cone-beam CT (CBCT) component for target guidance. Besides having poor soft-tissue contrast, CBCT unfortunately cannot provide molecular information due to its low sensitivity. Hence, there are extensive efforts to incorporate a molecular imaging component besides CBCT on these radiation therapy platforms. As an extension of these efforts, here we present a theranostic fluorescence tomography/CBCT-guided irradiator platform that provides both anatomical and molecular guidance, which can overcome the limitations of stand-alone CBCT. The performance of our hybrid system is validated using both tissue-like phantoms and mice ex vivo. Both studies show that fluorescence tomography can provide much more accurate quantitative results when CBCT-derived structural information is used to constrain the inverse problem. The error in the recovered fluorescence absorbance reduces nearly 10-fold for all cases, from approximately 60% down to 6%. This is very significant since high quantitative accuracy in molecular information is crucial to the correct assessment of the changes in tumor microenvironment related to radiation therapy.