Glycosaminoglycans are major constituents of the cancer cell surface and the tumor stroma. The heparan sulfate degrading enzyme heparanase, hyaluronan, and its receptor CD44 are up-regulated in breast cancer, generating a microenvironment that promotes tumor progression and metastasis. Recent experimental and clinical evidence shows that heparanase, hyaluronan, and CD44 regulate cancer cell proliferation, migration, and invasion, as well as tumor-associated angiogenesis and are correlated with patient survival. These findings suggest that they may be used as prognostic factors and targets for breast cancer treatment.