In this review, we focus on the metabolism of mammalian glycan-associated monosaccharides, where the vast majority of our current knowledge comes from research done during the 1960s and 1970s. Most monosaccharides enter the cell using distinct, often tissue specific transporters from the SLC2A family. If not catabolized, these monosaccharides can be activated to donor nucleotide sugars and used for glycan synthesis. Apart from exogenous and dietary sources, all monosaccharides and their associated nucleotide sugars can be synthesized de novo, using mostly glucose to produce all nine nucleotide sugars present in human cells. Today, monosaccharides are used as treatment options for a small number of rare genetic disorders and even some common conditions. Here, we cover therapeutic applications of these sugars and highlight biochemical gaps that must be revisited as we go forward.