Tumors are cellular masses formed through dynamic interactions between tumor cells and a mixed population of stromal cells. Crosstalk between oncogenic and adjacent stromal cells contributes to the formation of a “tumor microenvironment” influencing the tumor cell behaviors of proliferation, invasion, and metastatic spread throughout cancer progression. The composition and structure of the tumor microenvironment vary among different types of tumors and are extensively remodeled in close association with tumor advancement. The tumor microenvironment is composed not only of cellular compartments, such as endothelial cells, fibroblasts, inflammatory cells, and immune cells, but also of bioactive substances, including growth factors and the extracellular matrix. Hyaluronan (HA) is a major component of the extracellular matrix, and the degree of HA accumulation is strongly correlated with a poor prognosis in advanced cancer patients. Emerging evidence has suggested that HA creates a specific microenvironment that is favorable for tumor angiogenesis, invasion, and metastasis. This review highlights the prominent roles of HA as a modulator of the tumor microenvironment and addresses the recent advances regarding HA function in cancer stem cell niches.