Detailed protocols for the preparation of CdSe nanocrystals coated with a multishell structure of ZnS and their surface modification based on the successive ion layer adsorption and reaction method are described. The first phase of the synthesis produces a hydrophobic surface consisting of a TOPO/HDA ligand mixture. This is followed by a surface modification of the quantum dots (QDs) with 3-mercaptopropionic acid by the phase transfer method. The modified QDs become soluble in aqueous systems such as water or buffers for further biological applications.