Introduction: Significant efforts have focused on exploiting nanotechnology for unique solutions in clinical oncology. Here we present a radioluminescent nanophosphor (RLNP) intended to enhance the therapeutic effect of radiotherapy by augmenting the production of reactive oxygen species (ROS) with simultaneous photodynamic therapy (PDT). In this approach, RLNPs serve as a targeted carrier and activator of conjugated photosensitizers, such as protoporphyrin IX (PpIX). To impart molecular specificity, folic acid (FA) was chosen as a model targeting agent for the folate receptor (FR), which is overexpressed on many human cancer cells (e.g. ovarian, lung, breast, endometrial, renal, and colon). Materials & Methods: BaYF5 host nanocrystals were synthesized by the thermal decomposition method using lanthanide trifluoroacetates, barium acetylacetonate, oleic acid and 1-octadecene. In this system, optical emission can be tuned by selection of lanthanide dopants, such as Tb3+. To evaluate the radioluminescence of these nanophosphors a suspension of the particles was irradiated at 6 MV while an emission spectrum was obtained by a spectrograph coupled to an EM-CCD. In addition, poly(ethylene glycol) (PEG) was integrated in to this particle platform to improve in vivo biocompatibility and aid in internalization during receptor-mediated endocytosis. FA and PpIX were covalently linked via carboxyl groups to the RLNPs through a bifunctional DSPE-PEG-NH2 linker. RLNP-PEG-PpIX/FA conjugates were characterized by transmission electron microscopy (TEM) and UV spectroscopy. Results: Uniform cubic (~14 nm) nanocrystals were obtained by this process and characterized by TEM. Surface functionalization of the RLNPs with PEG produced hydrophilic and colloidal aqueous suspensions of the nanophosphors. Upon irradiation with clinical strength x-rays, strong emission peaks were observed at 489, 545, 586 and 619 nm with the BaYF5:Tb3+ RLNP. Of particular interest, emission at 545 nm coincides well with the absorbance of PpIX to activate ROS generation. Conjugation of both FA and PpIX was performed by N-hydroxysuccinimide (NHS) activation and confirmed by UV spectroscopy. Conclusion: Using this novel treatment approach, we seek to employ the depth penetration of X-rays coupled with RLNP luminescence to enable radiotherapy enhanced by PDT. Here, we have demonstrated the synthesis, chemical conjugation and radioluminescence emission/photosensitizer absorbance necessary for ROS generation. The successful development of this technique would provide an innovative tool with a synergistic cytotoxic effect and potential to lower therapeutic radiation doses. Furthermore, the PEG-coated nanophosphor platform developed here may serve as a novel molecular imaging probe. RLNPs may enable multimodal x-ray/optical imaging, as well as a wide range of other applications in molecular imaging and nanomedicine.