Two classes of mammalian glycosaminoglycans (GAGs) are distinguished: hyaluronic acid and chondroitin sulphate homopolymers, exhibiting identical repetitive building blocks, versus heparan and dermatan sulphate co-polymers, with differently substituted disaccharidic units. Evidence reported herein suggests that the latter compounds are positive co-factors of matrix assembly promoting the interaction of collagenous and non-collagenous proteins and inhibiting proteolytic activity. Homopolymers, on the contrary, are recognized as negative co-factors impairing the interaction of matrix proteins. The effect of GAGs on matrix assembly influences all the cell periphery because of trans-membrane relationships between submembranous cytoskeletal structures and the outer pericellular matrix. Molecular mechanisms involving GAGs in neoplastic transformation are proposed and discussed.