In the last few decades, hyaluronic acid (HA) has become increasingly employed as a biomaterial in both clinical and research applications. The abundance of HA in many tissues, together with its amenability to chemical modification, has made HA an attractive material platform for a wide range of applications including regenerative medicine, drug delivery, and scaffolds for cell culture. HA has traditionally been appreciated to modulate tissue mechanics and remodeling through its distinctive biophysical properties and ability to organize other matrix proteins. However, HA can influence cell behavior in much more direct and specific ways by engaging cellular HA receptors, which can trigger signals that influence cell survival, proliferation, adhesion, and migration. In turn, cells modify HA by regulating synthesis and degradation through a dedicated arsenal of enzymes. Optimal design of HA-based biomaterials demands full consideration of these diverse modes of regulation. This review summarizes how HA-based signaling regulates cell behavior and discusses how these signals can be leveraged to create cell-instructive biomaterials.