Nanoparticles have unique properties that can be exploited for cancer diagnosis and therapy. Intravenously injected nanoparticles accumulate predominantly in organs of the mononuclear phagocytic system, in addition to localizing in tumors and at sites of inflammation and infection. Accumulation in the liver and spleen lowers nanoparticles' ability to target pathological sites and compromises their use for radionuclide therapy. As described by Lee et al. in this issue of ACS Nano, radionuclide retention in liver and spleen can be greatly reduced by using liposomes that are surface-modified with esterase-cleavable radionuclide anchors. Because esterase activity is high in healthy tissues and low in tumors, the authors found that liposome-associated radioactivity rapidly cleared from the body and remained high only in tumors. The resulting images had high contrast-to-background ratios and remarkable tumor delineation. In this Perspective, we discuss these advances from early detection, cancer diagnosis, radionuclide therapy, and theranostics points of view. We outline the current clinical landscape of radionuclide targeting, imaging and therapy, and reflect on the roles that nanoparticles can play in these applications. We highlight the potential of nanoparticles that are responsive to endogenous stimuli for intraoperative imaging and, particularly, for individualized and improved radionuclide treatment. Taking these advances into account, future studies exploring the robustness and the clinical feasibility of nanomedicine-based radiotheranostic probes are eagerly awaited.