Quantum dots (QDs) need to be attached to other chemical species if they are to be used as biomarkers, therapeutic agents or sensors. These materials also need to disperse well in water and have well-defined functional groups on their surfaces. QDs are most often synthesized in the presence of ligands such as trioctylphosphine oxide, which render the nanoparticle surfaces hydrophobic. We present a complete protocol for the synthesis and water solubilization of hydrophobic CdSe/ZnS QDs using designer amphiphilic polymeric coatings. The method is based on functionalization of an anhydride polymer backbone with nucleophilic agents. Small functional groups, bulky cyclic compounds and polymeric chains can be integrated into the coating prior to solubilization. We describe the preparation of acetylene- and azide-functionalized QDs for 'click' chemistry. The method is universal and applicable to any type of nanoparticle stabilized with hydrophobic ligands able to interact with the alkyl chains in the coating in water.