Glycorandomization is a natural product derivatization strategy in which different sugar moieties are linked to the aglycone part of the naturally existing glycosides to create glycorandomized libraries. Sugars attached to the natural products are responsible for affecting their solubility, mechanism of action, target recognition, and toxicity and thus, by changing the sugar part, these properties could be modified. Glycorandomization can be done via two approaches (i) a synthetic approach known as neoglycorandomization, and (ii) chemoenzymatic approach including in-vitro and in-vivo glycorandomization. Glycorandomization can be a promising technology for the drug discovery that has proved its potential to improve pharmacokinetic (solubility) and pharmacodynamic profile (mechanism of action, toxicity, and target recognition) of the parent compounds. The substrate flexibility of glycosyltransferases and other enzymes towards sugars and/or aglycone substrates has made this technique versatile. Further, the enzymes can be altered by genetic engineering to generate glycorandomized libraries of diverse natural product scaffolds. This technique has the potential to produce new compounds that can be helpful to the mankind by treating the threatening disease states. This review covers the different strategies for glycorandomization as a tool in drug discovery and development. The fundamentals of glycorandomization, different types, and further development of differentially glycorandomized libraries of natural products and small molecule based drugs have been discussed.