Advances in early detection of disease and increases in lifespan necessitate new strategies to repair or replace damaged organs and tissues. My research is directed toward incorporating cues from the native environment and natural extracellular matrix (ECM) into the design of cell culture platforms and musculoskeletal tissue engineered constructs. By applying fundamental principles in cell and molecular biology, biomaterials, and biotransport phenomena, we are developing materials-based strategies to direct the behavior of transplanted or host cells within bone defects and interrogate the behavior of various cell populations in more physiologically relevant conditions. In this talk, I will present examples of our recent work in designing biomaterials from cells and natural and synthetic polymers to instruct cell fate and enhance tissue formation and function with applications in bone regeneration and repair.