Following the "detect-to-treat" strategy, by biological engineering, the emerging upconversion nanoparticles (UCNPs) have become one of the most promising inorganic nanomedicines, and their biomedical applications have gradually shifted from multimodal tumor imaging to highly efficient cancer therapy. The past few years have witnessed a three-stage development of UCNP-based nanomedicines. On one hand, UCNPs can optimize each clinical treatment tool (chemotherapy, photodynamic therapy (PDT), radiotherapy (RT)) by controlled drug delivery/release, near-infrared (NIR)-excited deep PDT, and radiosensitization, respectively, all of which contribute greatly to the optimized treatment efficacy along with minimized side effects. On the other hand, several individual treatments can be "smartly" integrated into a single UCNP-based nanotheranostic system for multimodal synergetic therapy, which can further improve the overall therapeutic effectiveness. Especially, UCNPs provide more-effective strategies for overcoming tumor hypoxia, thus leading to an ideal treatment efficacy for complete eradication of solid tumors. Finally, the critical issues regarding the future development of UCNPs are discussed to promote the clinic-translational applications of UCNP-based nanomedicines, as well as realization of our "one drug fits all" dream.