In the ten years since the first fibronectin type III (FN3) domain library was published, FN3 has continued to show promise as a scaffold for the generation of stable protein domains that bind to targets with high affinity. A variety of display systems, library designs and affinity maturation strategies have been used to generate FN3 domains with nanomolar to picomolar affinities. The first crystal structures of engineered FN3 molecules in complex with their targets have been solved, and structural studies of engineered FN3 have begun to reveal determinants of stability and to define zones that accept mutations with minimal trade-off between affinity and stability. CT-322, the first engineered FN3 to enter clinical development, is now entering Phase II trials for glioblastoma multiforme.