Noble metal nanoparticles, such as gold or silver nanoparticles and nanorods, exhibit unique photonic, electronic and catalytic properties. Functionalization of noble metal nanoparticles with biomolecules (e.g., protein and DNA) produces systems that possess numerous applications in catalysis, delivery, therapy, imaging, sensing, constructing nanostructures and controlling the structure of biomolecules. In this paper, the recent development of noble metal nanoparticle-biomolecule conjugates is reviewed from the following three aspects: (1) synthesis of noble metal nanoparticle-biomolecule systems by electrostatic adsorption, direct chemisorption of thiol derivatives, covalent binding through bifunctional linkers and specific affinity interactions; (2) the photonic properties and bioactivation of noble metal nanoparticle-biomolecule conjugates; and (3) the optical applications of such systems in biosensors, and medical imaging, diagnosis, and therapy. The conjugation of Au and Ag nanoparticles with biomolecules and the most recent optical applications of the resulting systems have been focused on. [4,5,8] are widely used to construct structures that possess unique electric, photonic and catalytic properties such as local surface plasmon resonance (LSPR) [7,[9][10][11], surface-enhanced Raman scattering (SERS) [12], and surface-enhanced fluorescence (SEF) [13,14]. There are two fundamental strategies used to prepare nanoparticles: bottom-up and top-down. The bottomup approach is a basic technique to prepare the metal nanoparticles by reducing their ions and the growth of the nanoparticles is usually stopped by an agent such as a surfactant or stabilizer. Bottom-up techniques include chemical reduction [15][16][17], photochemical reduction [18], electrochemical reduction [19], and templating [20] and thermal methods [21,22]. Bottom-up methods allow large-scale synthesis of the nanoparticles, but an obvious disadvantage is that the nanoparticles are usually of non-uniform size and shape compared with those produced by a top-down method. The top-down approach involves removing material from the bulk substrate to leave behind the desired nanostructures. Common top-down methods include photolithography, electron beam lithography, and nanosphere lithography (NSL) [23,24].Many biomolecules including proteins/enzymes/oligopeptides [7,25], antibody/antigens [1,26], biotin/streptavidin [23,24], and DNA/oligonucleotides/aptamers [6] have been immobilized on the surface of nanoparticles to form noble metal nanoparticle-biomolecule conjugates. The similar size of nanoparticles and biomolecules makes them rela-