Musculoskeletal tissue loss or damage resulting from trauma, surgery, or disease presents a significant medical challenge. Current therapies involving autografts and allografts are hindered by concerns over donor site morbidity and risks of disease transmission, respectively. Tissue engineering represents a promising strategy to develop ideal synthetic graft substitutes using biomaterials, cells, and biological factors alone or in combination. Nanocomposites based on polymers alone or in combination with other nanoscale materials constitute a unique class of biomaterials for the fabrication of tissue-specific architectures that closely mimic the structure and properties of native tissues. It is critical to understand cell–biomaterial interactions at the nanoscale involving the physical, chemical, and biological cues to engineer biomimetic structures for musculoskeletal tissue regeneration. This chapter aims to provide readers the rational design considerations as well as recent advances in the development of nanocomposites using various fabrication techniques for musculoskeletal tissue engineering.