Engineering the surface functionality of nanomaterials is the key to investigate the interactions between nanomaterials and biomolecules for potent biological applications such as therapy, imaging and diagnostics. My research has been orientted to engineer both of the surface monolayers and core materials to fabricate surface-functionalized nanomaterials through the synergistic multidisciplinary approach that combine organic chemistry, materials science and biology. This thesis illustrates the design and synthesis of the surface-funcitonalized quantum dots (QDs) and gold nanoparticles (AuNPs) for the fundamental studies and practical applications. For QDs, A new class of cationic QDs with quaternary ammonium derivatives was synthesized to provide permanent positive charge. The toxicity and stability of these cationic QDs were systematically investigated in cells. Furthermore, these cationic QDs were employed in the design of biosensor and fabrication of functional nanofibers. QDs with different surface functionalities were also used in the studies of controllable cellular uptake of nanoparticles and the construction of multifunctional nanocapsules. For AuNPs, cationic AuNPs were used to interact with proteins. The monolayer on AuNP surface can be tailored through host-guest chemistry to modulate the protein behaviors. Also, mass spectrometry was applied to detect the templation of AuNP monolayers to protein surface through molecular recognition. Taken together, nanomaterials with desired properties can be fabricated through surface functionalization approach to facilitate their use in biological system.