The evolutionary process of breast cancer involves progression through defined pathological and clinical stages, initiating with ductal hyperproliferation, subsequent development into in situ and invasive carcinomas, and finally metastatic disease. This chapter focuses on the intratumoral metabolism of the extracellular matrix (ECM) glycosaminoglycan, hyaluronan (HA), and the role that anabolic and catabolic products play in the initiation, progression, and invasion of breast cancer. The dynamic balance between HA synthesis and degradation within the tumor microenvironment plays an integral role in the complex, multistep process of carcinogenesis. Substantial preclinical work has elegantly elucidated the potential participation of both the synthetic and degradative enzymes in the metabolic processes of breast cancer. Tumor initiation, progression, and maintenance appear to be highly dependent on the accumulation of high MW HA within the breast cancer stroma, where it provides a hydrated growth matrix for tumor cells, promotes tumor survival by prevention of apoptosis, camouflages cancer cells from cytotoxic attack by host immunocompetent cells, and ultimately stimulates invasion. The specific signaling events induce neovascularization, lymphangiogenesis, and ECM degradation via the enhanced expression of matrix metalloproteinases. Numerous cellular ligands and molecules have been shown to participate in the process of HA metabolism and carcinogenesis of the breast, but a complete understanding of the significance with translation into clinical benefit requires substantially more work and elucidation.