Tissue engineering and regenerative medicine offer solutions to a number of compelling clinical problems that have not been adequately addressed through the use of permanent replacement devices. The challenge will be to select the optimal combination of a biomaterial scaffold, cells, and soluble regulators for a particular clinical problem. For many connective tissues of the musculoskeletal system, with microstructures that reflect the mechanical environment, it may be more advantageous to regenerate the tissue in vivo than to fully engineer the tissue in vitro for subsequent implantation. The porous material to be used as the scaffold to facilitate this regeneration needs to have certain pore characteristics, chemical composition and mechanical properties. One approach has been to employ substances that serve as analogues of the extracellular matrix of the tissue to be regenerated. For selected indications in which the supply of endogenous precursor cells is limited it may be more efficacious to employ a scaffold as a delivery vehicle for the cells rather than to inject the cells into the defect. Investigations of cell-scaffold interactions in vitro not only offer the opportunity for modification of scaffold composition and structure to improve the outcome in vivo, but also offer the opportunity to discover cell biological behaviour when cells grow in the three-dimensional tissue-like environment. Selected clinical applications may also require the implantation of regulatory proteins such as growth factors. That the action of such polypeptides released from biomaterials is short-lived has led to recent work wedding tissue engineering and gene therapy. Genes can be bound to certain biomaterial scaffolds to be released in vivo over extended periods (eg weeks) in order to genetically modify cells in the defect to produce the desired growth factors. Thus a new role for biomaterials is as a delivery vehicle for genes, as well as for cells and growth factors. These endeavours are notable particularly because there is a growing consensus that the challenge of developing biomaterials for tissue engineering, regenerative medicine, and gene therapy exceeds the challenge that was faced in the cell biological work that led to the proliferation of cells in vitro (in such a way that they retain their phenotypic characteristics) and in the genetic engineering that has led to the production of growth factors and cloning of their genes.