Tissue engineering strategies have utilized a wide spectrum of synthetic and naturally-derived scaffold materials. Synthetic scaffolds are better defined and offer the ability to precisely and reproducibly control their properties, while naturally-derived scaffolds typically have inherent biological and structural properties that may facilitate tissue growth and remodeling. More recently, efforts to design optimized biomaterial scaffolds have blurred the line between these two approaches. Naturally-derived scaffolds can be engineered through the manipulation of intrinsic properties of the pre-existing backbone (e.g., structural properties), as well as the addition of controllable functional components (e.g., biological properties). Chemical and physical processing techniques used to modify structural properties of synthetic scaffolds have been tailored and applied to naturally-derived materials. Such strategies include manipulation of mechanical properties, degradation, and porosity. Furthermore, biofunctional augmentation of natural scaffolds via incorporation of exogenous cells, proteins, peptides, or genes has been shown to enhance functional regeneration over endogenous response to the material itself. Moving forward, the regenerative mode of action of naturally-derived materials requires additional investigation. Elucidating such mechanisms will allow for the determination of critical design parameters to further enhance efficacy and capitalize on the full potential of naturally-derived scaffolds.