Colloidal fluorescent semiconductor nanocrystals, named “quantum dots”, possess unique features, such as a tunable peak wavelength (according to their composition and their size) or a large absorption cross-section, that make them very attractive for biomedical imaging. Nevertheless, typical syntheses provide nanoparticles capped with hydrophobic ligands. To be used in long-term bioexperiments, they have thus to be modified to exhibit essentially a high colloidal stability in aqueous conditions, but also a low non-specific adsorption, a small size and functionalization moities. As all of these properties are controlled by the layer of coating ligands, we designed a bidentate monozwitterionic ligand, to first address the need of small-sized and antibiofouling hydrophilic probes. But the corresponding quantum dots revealed to be unstable in highly diluted conditions and difficult to functionalize. To further increase the affinity between the nanoparticles and their surrounding ligands, we synthesized a multidentate polyzwitterionic ligand, issued from the copolymerization of a bidentate monomer and a monozwitterionic one. The nanocrystals passivated by this polymeric ligand showed an exceptional colloidal stability, regardless of the medium conditions (pH, salinity, dilution, and biological environment), and we demonstrated the affinity of the polymer exceeded by three orders of magnitude that of the bidentate ligand. The synthesis of the multidentate polyzwitterionic ligand proved also to be easily tunable and allowed the facile introduction of reacting moieties. Further functionalization of the corresponding quantum dots with biomolecules led to successful specific targeting, which could be confirmed, as an example, through FRET experiments.