Much effort has been made in the development of biomaterials that synthetically mimic the dynamics of the natural extracellular matrix in tissues. Most of these biomaterials specifically interact with cells, but lack the ability to adapt and truly communicate with the cellular environment. Communication between biomaterials and cells is achieved by the development of various materials with enzyme-responsive moieties in order to respond to cellular cues. In this perspective, we discuss different enzyme responsive systems, from surfaces to supramolecular assemblies. Additionally, we highlight their further prospects in order to create, inspired by nature, fully autonomous adaptive biomaterials that display dynamic reciprocal behavior. This Perspective shows new strategies for the development of biomaterials that may find broad utility in regenerative medicine applications, from scaffolds for tissue engineering to systems for controlled drug delivery.