The use of naturally occurring materials as scaffolds to support cell growth and proliferation significantly impacted the origin and progress of tissue engineering and regenerative medicine. However, the majority of these materials failed to provide adequate cues to guide cell differentiation toward the formation of new tissues. Over the past decade, a new generation of multifunctional and smart natural-based materials has been developed to provide biophysical and biochemical cues intended to specifically guide cell behavior. In this chapter, the use of extracellular matrix proteins and blood-derivatives intrinsic capacity to mimic the biophysical and biological characteristics of native tissues is reviewed. Furthermore, the design of a variety of nanostructures using the well-explored characteristics of nucleic acids is summarized. In the second section, the exploitation of supramolecular chemistry to create new dynamic functional hydrogels that mimic the extracellular matrix structure and/or composition is surveyed. Then, the incorporation of nanoelements in polymeric networks for the design of smart nanocomposite materials with tailored functionalities to guide cell behavior is introduced. Finally, the future perspectives in the development of new biomaterials for tissue engineering and regenerative medicine are presented.