Currently, nanomaterials are of widespread use in daily commercial products. However, the most-promising and potentially impacting application is in the medical field. In particular, nanosized noble metals hold the promise of shifting the current medical paradigms for the detection and therapy of neoplasms thanks to the: (i) localized surface plasmon resonances (LSPRs), (ii) high electron density, and (iii) suitability for straightforward development of all-in-one nanoplatforms. Nonetheless, there is still no clinically approved noble metal nanomaterial for cancer therapy and diagnostics. The clinical translation of noble metal nanoparticles (NPs) is mainly prevented by the issue of persistence in organism after the medical action. Such persistence increases the likelihood of toxicity and the interference with common medical diagnoses. Size reduction to ultrasmall nanoparticles (USNPs) is a suitable approach to promoting metal excretion by the renal pathway. However, most of the functionalities of NPs are lost or severely altered in USNPs, jeopardizing clinical applications. A ground-breaking advance to jointly combine the appealing behaviors of NPs with metal excretion relies on the ultrasmall-in-nano approach for the design of all-in-one degradable nanoplatforms composed of USNPs. Such nanoarchitectures might lead to the delivery of a novel paradigm for nanotechnology, enabling the translation of noble metal nanomaterials to clinics to treat carcinomas in a less-invasive and more-efficient manner. This Review covers the recent progresses related to this exciting approach. The most-significant nanoarchitectures designed with the ultrasmall-in-nano approach are discussed, and perspectives on these nanoarchitectures are provided.