Syndecans are transmembrane heparan sulfate proteoglycans involved in the regulation of cell growth, differentiation, adhesion, neuronal development, and lipid metabolism. Syndecans are expressed in a tissue-specific manner to facilitate diverse cellular processes. As receptors and co-receptors, syndecans provide promising therapeutic targets that bind to a variety of physiologically important ligands. Negatively charged glycosaminoglycan chains of syndecans, located in the extracellular compartment, are critical for such binding. Functions of syndecans are as diverse as their ligands. For example, hepatic syndecan-1 mediates clearance of triglyceride-rich lipoproteins. Syndecan-2 promotes localization of Alzheimer's amyloid Aβ peptide to the cell surface, which is proposed to contribute to amyloid plaque formation. Syndecan-3 helps co-localize the appetite-regulating melanocortin-4 receptor with its agonist, leading to an increased appetite. Finally, syndecan-4 initiates the capture of modified low-density lipoproteins by macrophages and thereby promotes the atheroma formation. We hypothesize that syndecan modifications such as desulfation of glycosaminoglycan chains may contribute to a wide range of diseases, from atherosclerosis to type 2 diabetes. At the same time, desulfated syndecans may have beneficial effects, as they can inhibit amyloid plaque formation or decrease the appetite. Despite considerable progress in understanding diverse functions of syndecans, the complex physiological roles of this intriguing family of proteoglycans are far from clear. Additional studies of syndecans may potentially help develop novel therapeutic approaches and diagnostic tools to alleviate complex human diseases such as cardiovascular and Alzheimer's diseases.