Neoglycorandomization is a chemoselective glycodiversification method inspired by the alkoxyamine-based ‘neoglycosylation’ reaction first described Peri and Dumy. This reaction proceeds via an oxy-iminium intermediate to ultimately provide the more thermodynamically-favored closed ring neoglycoside. The neoglycosylation reaction is compatible with a wide range of saccharide and aglycon functionality where neoglycoside anomeric stereospecificity is a thermodynamically-driven. Importantly, structural and functional studies reveal neoglycosides to serve as good mimics of their O-glycosidic comparators. The first neoglycorandomization proof of concept focused upon digitoxin where the rapid generation and cancer cell line cytotoxicity screening of 78 digitoxigenin neoglycosides revealed unique analogs with improved anticancer activity and reduced potential for cardiotoxicity. This platform has since been automated and used as an effective medicinal chemistry tool to modulate the properties of a range of natural products and pharmaceutical drugs.