Recent advances in genetic engineering, such as Ext1 knockout models, have revealed that Glycosaminoglycans (GAGs) are indispensable for gastrulation, neurogenesis, and bone formation. Beyond their structural role in cartilage, GAGs function as critical signaling modulators by interacting with receptors like TLR2/4 and STING. Current research highlights that specific sulfation patterns create functional domains essential for protein binding, offering pathways forantithrombotic drugs and cancer diagnostics (e.g., VAR2CSA). The frontier of GAG-based medicine lies in correcting these sulfation structures using small molecules or RNA oligonucleotides. However, achieving precision therapy requires overcoming two major hurdles: developing single-cell GAG analysis and creating antibodies specific to disease-associated variants—milestones expected within the next decade.