The design of hyaluronic acid (HA)-based hydrogel scaffolds to elicit highly controlled and tunable cell response and behavior is a major field of interest in developing tissue engineering and regenerative medicine applications. This review will begin with an overview of the biological context of HA, which is needed to better understand how to engineer cell-matrix interactions in the scaffolds via the incorporation of different types of signals in order to direct and control cell behavior. Specifically, recent methods of incorporating various bioactive, mechanical and spatial signals are reviewed, as well as novel HA modifications and crosslinking schemes with a focus on specificity.