There is a rapidly increasing interest in developing stimuli-responsive nanomaterials for treating a variety of diseases. By enabling the activation of function locally at the sites of interest, it is possible to increase therapeutic efficacy significantly while simultaneously reducing adverse side effects. While there are many sophisticated nanomaterials available, they are many times highly complex and not easily transferrable to industrial scales and clinical settings. However, hyaluronic acid-based nanomaterials offer a compelling strategy for reducing the complexity of nanomaterials while retaining several desirable benefits such as active targeting and stimuli-responsive degradation. In this report, we cover the basic properties of hyaluronic acid, its binding partners, and natural routes for degradation by hyaluronidases—hyaluronic acid-degrading enzymes—and oxidative stresses. We then cover recent advances in designing hyaluronic acid-based, actively targeted, hyaluronidase- or reactive oxygen species-responsive nanomaterials for both diagnostic imaging and therapeutic delivery that go beyond merely the classical targeting of CD44.