As a bridge between individual atoms and large plasmonic nanoparticles, ultrasmall (core size <3 nm) noble metal nanoparticles (UNMNPs) have been serving as model for us to fundamentally understand many unique properties of noble metals that can only be observed at an extremely small size scale. With decades' efforts, many significant breakthroughs in the synthesis, characterization and functionalization of UNMNPs have laid down a solid foundation for their future applications in the healthcare. In this review, we aim to tightly correlate these breakthroughs with their biomedical applications and illustrate how to utilize these breakthroughs to address long-standing challenges in the clinical translation of nanomedicines. In the end, we offer our perspective on the remaining challenges and opportunities at the frontier of biomedical-related UNMNPs research. (C) 2018 Elsevier Ltd. All rights reserved.