Over the past decade quantum dots (qdots) have emerged as a premier biological labeling tool due to their unique photophysical properties. In order to take advantage of these properties, a lot of surface chemistry design work needs to take place due to the need of phase transfer to aqueous buffers, as well as the need to preserve both photophysical and colloidal stability. This chapter first briefly reviews a number of functionalization strategies available to researchers, and then focuses on our groups strategy. In particular, the use the amino acid L-histidine to facilitate both phase trasfer, ligand exchange, as well as direct biological functionalization. The binding mechanism and properties of the histidine-capping at the qdots is reviewed, as well as the use of resonance energy transfer (FRET and BRET) to probe the abiotic-biotic interface.