Interactions between glycans and proteins are central to many of the regulatory processes within biology. The development of analytical methodologies that enable structural characterization of glycosaminoglycan oligosaccharides has fostered improved understanding of the specificity of these biomolecular interactions. This facilitates an appreciation in understanding how changes in GAG structure can regulate physiology as well as pathology. While there are various techniques for studying the interaction of GAGs with proteins, in this chapter we focus on two approaches. First, an integrated analytical methodology, surface non-covalent affinity mass spectrometry (SNA-MS), is described to isolate, enrich, and sequence tissue-derived GAGs that bind to specific proteins. The broad applicability of this powerful platform offers an insight into how changes in cell-surface and extracellular GAG composition and sequence influences the ability of cells and tissues to dynamically alter responses to signaling molecules. Thus, this approach provides a window into understanding how changes at a molecular level manifest with respect to cellular phenotype. Second, surface plasmon resonance, or SPR, represents an additional platform for the study of protein-polysaccharide interaction, specifically for measuring the binding between GAG chains and proteins.