Abstract Fluorescent metal nanoclusters (FMNCs), one of the promising functional nanomaterials, have aroused great interest in diverse areas due to their unique characteristics, such as ultrasmall size, high fluorescence, excellent photophysical and chemical stability, good biocompatibility, and tuneable emissions. Many methods have been developed to prepare the FMNCs. Among them, the biomolecule‐directed approach, which could produce FMNCs with high water‐solubility, good biocompatibility, enhanced fluorescence, and rich surface chemistry for conjugation has attracted enormous attention. In this review, we highlight the substantial progress in protein‐ and peptide‐directed approaches to varieties of FMNCs. The synthetic protocols and potential formation mechanisms are well summarized. Selected key applications, ranging from biological and chemical detection to cellular and in vivo imaging, are also discussed. Finally, the current challenges, as well as future perspectives, are briefly discussed. The lessons from these case studies would provide a valuable guide to designing nanomaterials with desired or even personalized functions in the future.