As a prominent tool in regenerative medicine, tissue engineering (TE) has been an active field of scientific research for nearly three decades. Clinical application of TE technologies has been relatively restricted, however, owing in part to the limited number of biomaterials that are approved for human use. While many excellent biomaterials have been developed in recent years, their translation into clinical practice has been slow. As a consequence, many investigators still employ biodegradable polymers that were first approved for use in humans over 30 years ago. During normal development tissue morphogenesis is heavily influenced by the interaction of cells with the extracellular matrix (ECM). Yet simple polymers, while providing architectural support for neo-tissue development, do not adequately mimic the complex interactions between adult stem and progenitor cells and the ECM that promote functional tissue regeneration. Future advances in TE and regenerative medicine will depend on the development of "smart" biomaterials that actively participate in the formation of functional tissue. Clinical translation of these new classes of biomaterials will be supported by many of the same evaluation tools as those developed and described by Professor David F. Williams and colleagues over the past 30 years.