Many natural products derive their biological activities from their sugar components. Changing the structures of these sugar moieties can profoundly impact the biological properties of the fully assembled compounds. Realizing the potential of this chemistry requires both an understanding of the biosynthetic pathway of each sugar and a detailed mechanistic knowledge of the key enzymes. We and others have thus been devoted to unravelling the biochemical principles underlying the assembly of glycosylated natural products wherein a core set of enzyme activities mix and match to synthesize structurally diverse secondary metabolites. This work has laid the foundation for our more recent studies of the biosynthesis of sugar-derived natural products and revealed several cases involving unique and interesting chemistry. For example, the key transformation converting cytosylglucuronic acid (CGA) to cytosyl-4'-keto-3'-deoxy-D-glucuronic acid during the biosynthesis of blasticidins is a radical initiated 1,2-diol dehydration catalyzed by the radical SAM enzyme BlsE. Likewise, C-glycosylation appears to be required for the introduction of a C–C bond between pyranose and furanose bearing precursors during the biosynthesis of herbicidin thereby generating its tricyclic structure. However, the herbicidin biosynthetic gene cluster does not contain a typical glycosyltransferase. Instead, it was found that the C–C coupling reaction proceeds in two-stages resulting in net C5'-glycosylation between ATP and UDP-glucuronic acid catalyzed by two NAD-dependent enzymes. The biosynthetic roles of selected enzymes in these two systems, their mechanisms of catalysis, and the insights they can offer for understanding natural product biosynthesis and radical SAM enzymology will be discussed.