Proteoglycans (PGs) are major components of all mammalian tissues, being present ubiquitously on cell surfaces and within extracellular matrices (ECM). They play vital roles in mammalian physiology and have been implicated in many disease processes. PGs comprise a single core protein with one or more glycosaminoglycan (GAG) chains attached where these un-branched polysaccharides are composed of repeating disaccharide units that show considerable diversity in their disaccharide composition, glycosidic linkages, and levels/positions of sulfation (1, 2). GAGs, therefore, contain huge numbers of structural permutations (even in the same chain), representing a vast possible array of diverse structures that can determine the fate of local environments (3): i.e., through their modulation of protein-binding and activity. Thus, PGs constitute a tissue and region-specific microenvironment of sugar molecules, both within the ECM and at the cell-matrix interface, which acts as a local regulator of tissue function and homeostasis. As described below, it is our opinion that this proteoglycan "glycomatrix" plays a key role in the regulation of the immune system by acting as a molecular postcode that controls local immune function (4). Here we will illustrate this with examples of the effects of PGs/GAGs on the immune system in the eye, heart, kidney, and lung. In particular, we will focus on recent evidence that GAGs can positively and negatively regulate the alternative pathway of complement and suggest how the dysregulation of this aspect of innate immunity may contribute to disease processes in a tissue-specific manner. © 2013 Clark, Bishop and Day.