A new type of ligand chemistry, with a zwitterionic carboxybetaine headgroup and a bidentate thiol end group (CBSS), is introduced to promote the stability of quantum dots (QDs) with targeting capability. Results show that QDs are stable over a broad range of pH values after surface modification. Surface binding assays and cellular internalization studies show that QDs capped with CBSS exhibit low nonspecific adsorption. The CBSS ligand also allows the conjugation of highly specific targeting ligands while effectively maintaining the nonfouling background. This QD chemistry offers a unique approach to presenting abundant functional groups for ligand immobilization in a thin layer with an ultralow background and holds significant potential for imaging applications.