Biotribology is the science of biological surfaces in sliding contact encompassing the concepts of friction, wear, and lubrication of interacting surfaces. This bioscience field has emerged from the classical field of tribology and is of paramount importance to the normal function of numerous tissues, including articular cartilage, blood vessels, heart, tendons, ligaments, and skin. Surprisingly, relatively little attention has been given to the restoration of surface characteristics in the fields of tissue engineering and regenerative medicine-the science of design and manufacture of new tissues for the functional restoration of impaired or diseased organs that depend on inductive signals, responding stem cells, and extracellular matrix scaffolding. Analogous to ancient civilizations (c. 3000 B.C.) that introduced wheeled vehicles, sledges for transporting heavy blocks, and lubricants, modern biotribologists must aim to restore surface characteristics to regenerated tissues and develop novel biomaterials with optimal tribological properties. The objective of this article is to highlight the significance of functional biotribology in the physiology of body surfaces and provide a comprehensive overview of unresolved issues and controversies as it relates to regenerative medicine. Specific attention is placed on the molecular basis of lubrication, mechanical and biochemical regulation of lubricating molecules, and the need to study wear processes in articular cartilage, especially in light of degenerative diseases, such as osteoarthritis. Surface engineering of replacement tissues exhibiting low friction and high wear resistance is examined using articular cartilage as an illustrative model system.