Despite advances in chemotherapeutic regimens, the treatment of metastatic cancer remains a challenge. A key problem with chemotherapy drugs is nonspecific drug distribution, resulting in low tumor concentrations and systemic toxicity. The holy grail of clinical cancer research has been to establish more specific ways of directing therapeutics to tumors, whether through more targeted anti-cancer agents or via the method of delivery. Many tumor cells show upregulated expression of receptors for the polysaccharide hyaluronan (HA), resulting in HA having a high affinity for tumors. This observation has led to the preclinical development of HA-cytotoxin bioconjugates that utilize HA as the tumor recognition moiety. The primary challenges have been organ-directed toxicity and limited efficacy. An alternative, simpler strategy has been to use the large volumetric domain of HA to entrain small chemotherapeutic drugs within the HA matrix. The resultant HA/drug formulation accumulates in the microvascular of the tumor, forming a microembolism that increases drug retention at the tumor site and allows for active tumor uptake through HA receptors. Clinical trials of HA formulations of three anti-cancer drugs have been undertaken and have demonstrated that such formulations are safe and efficacious. Within these formulations we postulate that HA is acting as a novel excipient, capable of improving the therapeutic index of the active anti-cancer agent.