Conventional photodynamic therapy (PDT) has proved effective in the management of primary tumors and individual metastases. However, most cancer mortality arises from wide-spread multiple metastases. The latter has thus become the principal target in oncology, and X-ray induced photodynamic therapy (XPDT or PDTX) offers a great solution for adapting the PDT principle to deep tumors and scattered metastases. Developing agents capable of being excited by X-rays and emitting visible light to excite photosensitizers is based on challenging physical and chemical technologies, but there are fundamental biological limitations that are to be accounted for as well. In the present review, we have established eight major groups of safety determinants of NPs encompassing 22 parameters of clinical applicability of XPDT nanoparticulate formulations. Most, if not all, of these parameters can be accounted for and optimized during the design and development of novel XPDT nanoparticles.