Advances in regenerative medicine and in modern biomedical therapies are fast evolving and set goals causing an upheaval in the field of materials science. This review discusses recent developments involving the use of biopolymers as smart materials, in terms of material properties and stimulus-responsive behavior, in the presence of environmental physico-chemical changes. An overview on the transformations that can be triggered in natural-based polymeric systems (sol–gel transition, polymer relaxation, cross-linking, and swelling) is presented, with specific focus on the benefits these materials can provide in biomedical applications.