Carbohydrates are integral components of structural glycoproteins, proteoglycans, immunoglobulins, cell-adhesion and recognition molecules, lectins, transport proteins, cytoplasmic proteins, nucleoproteins, and hormones. The great heterogeneity of carbohydrates, due to the variable number of monosaccharides present in oligo- and polysaccharides, the anomericity and the position of the glycosidic linkage, as well as the branching and the substitution of hydroxyl and amino groups with sulfate, phosphate, or acetyl groups, results in a broad range of structural diversity and biological activity as compared with proteins and nucleic acids. Recent advances on the structure-function relationship have revealed the importance of carbohydrates in vivo, whereas data on their role in biological systems have expanded the classical sciences of biology and biochemistry and opened new areas in diagnosis, treatment, and prognosis. This communication highlights some general principles and concepts of glycobiology with reference to the importance of glycosylation in normal control mechanisms, cancer, host-pathogen interactions, and bacterial infections. Proteoglycans are considered to be the major family of structural glycoconjugates. They are heavily glycosylated and highly charged macromolecules consisting of glycosaminoglycan (GAG) and oligosaccharide chains covalently bound to a protein core. Aggregates of the cartilage PGs with hyaluronan (HA) contribute to the load-bearing properties of cartilage. PGs are essential extracellular components of connective tissues, and most of them have been studied therein, but recent advances have identified new families of much smaller cell surface PGs (Kjellen and Lindahl, 1991). Via specific interactions of GAGs with matrix effector molecules, such as growth factors and/or membrane receptors, PGs participate in several cellular events, such as cell proliferation, differentiation, adhesion, and migration, acting either directly on cells or modulating growth factor activities. We have shown that PGs, via their GAGs, affect cell proliferation and differentiation in human malignant mesothelioma (HMM) cells and that the intracellular signaling process is mediated through a tyrosine phosphokinase activity which requires the interaction of GAGs with growth factors and their receptor (Tzanakakis et al., 1995, 1997). Recently developed HPLC and capillary electrophoresis methods for GAG analysis and structural characterization have also helped in the diagnosis of HMM in pleural effusions and exfoliation syndrome of the eye (Karamanos et al., 1994a, 1997a; Lamari et al., 1998) and to explain that the GAG sequence is nonrandom and biosynthetically regulated (Karamanos et al., 1995) as well as elucidating the biological and physiological properties of GAGs (Karamanos et al., 1994b). Cell surface glycoconjugates play a major role in cell-cell and cell-molecule recognition events. In many cell adhesion molecules of the, nervous system, the peripheral glycoprotein (PO), which is the smallest member of the immunoglobulin superfamily, is involved in critical steps of the pathogenesis of nerve diseases, such as multiple sclerosis. The N-linked oligosaccharides of PO contain the L2/HNK-1 epitope (3-sulfoglucuronic acid). The absence of this epitope results in the failure of cellular aggregation (Filbin and Weissmann, 1991). We found the HNK-1 epitope to be present in invertebrate PGs and we have developed both immunological and HPLC methods for its identification (Karamanos et al., 1994c). Mucins make up another category of GPs with protective effects. They are secreted by the mucosal cells (gastrointestinal, respiratory, and genitourinary). Mucins have molecular weights greater than one million daltons and more than 80% of their dry weight is O-linked carbohydrates which are heavily sialylated and/or sulfated. Mucins lubricate and protect the mucosal epithelium reducing pathogen adhesion to epithelial surfaces. Secreted mucins which bind to pathogens may cover antigenic epitopes, blocking normal antibody response. It is clear that changes in mucin carbohydrates are associated with disease and with susceptibility to infection. Such changes are useful diagnostic markers for a variety of cancers. Thus, the presence of sialylated tumor-related mucin correlates with malignant and metastatic potential. In this area we have developed sensitive methodology to determine the two main sialic acid types (Neu5Ac and Neu5Gc) (Karamanos et al., 1990). Investigation to establish whether these sialic acids may help as an important tumor marker is in progress. The significance of glycosylation in normal control mechanisms may be seen from many known GPs where changes in the carbohydrates are consistently associated with disease development. The tissue plasminogen activator (t-PA) is a serine protease that contributes to the conversion of plasminogen to plasmin. T-PA is very useful in dissolving blood clots in heart attacks and strokes, and the rate of plasminogen activation depends on the presence in oligosaccharides of Asn-184 (Wittwer, 1989). Glycoconjugates are also involved in host-pathogen interactions and bacterial infections. Thus, viral GPs are synthesized by host cells with glycosylation not distinguishable from those of host GPs. Hepatitis B, influenza viruses, and HIV virus all contain such GPs. In HIV virus, GPs are highly N-glycosylated (20-25 potential glycosylation sites) and particularly in gp 120 the carbohydrate content amounts to 50% of the total weight. These glycoconjugates in the surface of parasitic protozoa play a critical role in immune evasion, complement resistance, parasitic internalization, and differentiation. Because of their unique glycan structures, distinct from the host, they may constitute easy targets for drug therapy and vaccine development. In the area of bacterial infections, recent studies have shown that the major components of the extracellular slime layer of S. epidermidis are composed of discrete glycoconjugates. The main polysaccharide component can be used to identify the infection in hospitalized immunocompromised patients (Karamanos et al., 1991b). The correlation of glycosylation with disease can be seen from the increasing number of clinical diagnostic procedures based on the use of lectins to detect abnormal glycosylation on the surface of malignant cells, and the development of anticancer agents which inhibit the glycosylation process. The increase of agalactosyl IgG (Fc N-glycan lacking terminal galactose) in the total IgG correlates with increased disease activity in a number of diseases, such as rheumatoid arthritis and Crohn's disease.