Hyaluronan not only is an important structural component of extracellular matrices but also interacts instructively with cells during embryonic development, healing processes, inflammation, and cancer. It binds to several different types of cell surface receptors, including CD44, thus leading to co-regulation of important signaling pathways, notably those induced by activation of receptor tyrosine kinases. Consequently, interactions of both stromal and tumor cell-derived hyaluronan with tumor cells play important cooperative roles in several aspects of malignancy. This review focuses on cell autonomous hyaluronan-tumor cell interactions that lead to activation of receptor tyrosine kinases and enhanced drug resistance. Particular emphasis is placed on the role of hyaluronan-CD44 interactions in drug transporter expression and activity, especially in cancer stem-like cells that are highly malignant and resistant to chemotherapy. Antagonists of hyaluronan-CD44 interaction, especially small hyaluronan oligomers, may be useful in therapeutic strategies aimed at preventing tumor recurrence from these therapy-resistant sub-populations within malignant cancers.