Increasing demand for donor organs calls for alternative organ and tissue sources. Tissue engineering combines the principles of bioengineering, cell transplantation and biomaterials engineering to create platforms that resemble as closely as possible the body's own native tissues in order to stimulate tissue and organ regeneration for transplantation. Basic building blocks such as stem cells and scaffolds, which may act as inert structural supporting frameworks and/or delivery vehicles for biologically active molecules, may be superimposed in various ways to create suitably specific scaffolds able to accelerate and guide new functional tissue formation. The emergence of nanotechnology and its integration into the field of tissue engineering (‘nano-engineering’) has revolutionized the approach to fabricating tissues and organs. Scaffolds with nanostructured surfaces closely mimic the molecular structure of natural tissues and organs, enabling finer control over cellular positioning, organization and interactions. This chapter focuses on the main determinants for successful engineering of tissues and whole organs. Particular attention is paid to the importance of stem cells and micro- and nanoscale features which, when orchestrated correctly, can act in synergy to recuperate lost function and aesthetics. A new generation of silica nanocomposite scaffolds based on POSS nanoparticle-integrated poly(carbonate urea)urethane (POSS-PCU) will be critically debated in the context of their materials properties and their immense clinical translational potential, exemplified via the world's first in-human transplantation of a fully synthetic tracheal replacement and several more applications.