Proteoglycans (PGs), glycosaminoglycans (GAGs) and hyaluronan as a free GAG, have unique structural characteristics which enable them via specific interactions with matrix proteins and cell surface receptors to regulate key tumor cell functions and thus to affect cancer growth and progression. This article explores the many layers of interdependent signaling among transformed colon epithelial cells, neighboring stromal cells and their respective PGs / GAGs components along the insidious and often deadly route of colon cancer progression. Specifically addressed is the altered deposition of PGs / GAGs by colon cancer cells; the effects of these malignant cells on gene expression and biosynthesis of PGs / GAGs of the surrounding stromal cells and the signaling pathways involved, with the utmost goal to highlight potential therapeutic targets in the rapidly developing field of glycan-based therapy.