Abstract: Natural products are one of the most important sources for druggable lead compounds given their diverse structures and activities. Nevertheless, very few of them can be directly developed to drugs. The undesirable druggability of natural products result from their weaker activity, lower aqueous solubility and poorer stability. Since improving druggability by chemical modifications is restricted by the limited access to the complex structures of natural products, enzymatic modification has gradually become one of important tools for the structural modification of natural products. Meanwhile, since enzymatic glycosylation by glycosyltransferases has shown certain advantages such as excellent regio- and stereo-selectivity, high catalytic efficiency and mild conditions. It has been a promising route for the improvement of druggability for natural products. In the present review, we summarize different glycosyltransferases and their application for structural modification of natural products as well as the challenges issues involved in the glycosylation, which provides a general perspective on the enzymatic modification of natural products for the improvement of their draggability.