The regeneration of human body tissues is complex and complicated, involving the participation of multiple cells, the extracellular matrix (ECM) and bio-signals as well as their interactions. To promote tissue regeneration, different tissue engineering strategies have been developed by many researchers. Scaffold-based tissue engineering, which employs highly porous scaffolds formed by using suitable biomaterials and fabrication techniques as artificial ECM, has played a dominant role in the tissue engineering field. Due to complexity in the tissue regeneration process and different requirements for specific regenerative therapy, multiple functions are mostly required for advanced tissue engineering scaffolds, which are expected to provide comprehensive cues in structure and physical, chemical and biological properties for better controlling cell behaviour and for enhancing tissue regeneration. On the basis of our own research, this chapter briefly reviews materials in tissue engineering and scaffold manufacturing technologies, outlines multiple requirements for tissue engineering scaffolds, presents designs of multifunctional scaffolds, and gives case studies for developing smart multifunctional scaffolds. Compared to conventional tissue engineering scaffolds, multifunctional scaffolds formed by different fabrication techniques possess distinctive multiple capabilities and exhibit respective superior performance or great potential for different regenerative/therapeutic applications.