Water-soluble, highly fluorescent, silanized semiconductor nanocrystals with different surface charges were synthesized. To covalently attach the nanocrystals to biological macromolecules with a variety of mild coupling chemistries, the outermost siloxane shells were derivatized with thiol, amino, or carboxyl functional groups. Single- or double-stranded DNA was coupled to the nanocrystal surfaces by using commercially available bifunctional cross-linker. Conjugation had little effect on the optical properties of the nanocrystals, and the resulting conjugates were more stable than previously reported systems. By using the strategies developed in this study, most biomolecules can be covalently coupled to semiconductor nanocrystals. These nanocrystal-DNA conjugates promise to be a versatile tool for fluorescence imaging and probing of biological systems.