Recent advances in nanomaterials have produced a new class of fluorescent labels by biocognition molecules to fluorescent noble-metal nanoclusters such as Au and Ag. In particular, the emission wavelength of metallic
nanoclusters can be tuned by changing the capping molecules, and a single light source is needed for simultaneous excitation of all different-emissive nanoclusters, which is similar to semiconductor quantum dots. In this review, we highlight the recent advances in synthesis approaches, biomolecular conjugation and its biomedical application. Fabricating the color-emitting metal nanoclusters using the template-based synthesis (i.e., dendrimer, oligonucleotide, proteins, polyelectrolyte, and polymer) and monolayer-protected nanocluster (MPC) synthesis (i.e., dihydrogen lipoic acid and mercaptoundecanoic acid) are described. High-quality nanoclusters are also more biocompatible and stable against photobleaching compared with organic dyes. These novel optical properties render the fluorescent noble-metal nanoclusters ideal fluorophores for multicolor and multiplexing applications in biomedical engineering and molecular biotechnology.