Articular joints are one of the most robust bearing systems found in the natural world. Healthy joints can withstand over 100 million shearing and compressive cycles without wear. This phenomenal lubrication is due to both the cartilage that forms the bearing surface and the synovial fluid that lubricates the joint. However, in cases of joint disease such as osteoarthritis, chemical and mechanical changes in the cartilage and synovial fluid compromise the lubrication of the entire joint. Understanding the lubrication mechanisms of synovial fluid and how they are altered in disease and under various therapeutic interventions is critical for developing osteoarthritis therapies that restore joint functionality. This thesis presents studies on synovial fluid lubrication at both the molecular and tissue scale. Under shear, aggregates form within the synovial fluid that lubricates articular joints. This dissertation investigates the composition and lubricating role of these aggregates (Chapter 2). Our results reveal that the globular protein albumin is the primary molecule involved in aggregate formation. This finding is relevant for artificial joint lubrication because protein aggregates have been attributed with improving wear protection between metal surfaces in-vitro. Lubricin is a molecule in synovial fluid that shows therapeutic potential as a treatment for osteoarthritis but is challenging to produce in large volumes. Synthetic lubricin-mimetics that imitate both the lubrication and surface attachment of natural lubricin offer a promising alternative. In this dissertation, the interaction between fibronectin (a cartilage surface protein that interacts with lubricin) and a lubricin-mimetic was characterized and their combined tribological behavior was monitored (Chapter 3). The mimetic lubricin was found to interact with fibronectin to provide lubrication and wear protection comparable to natural lubricin. Hyaluronic acid viscosupplementation is a prevalent treatment for osteoarthritis. However, while high viscosity is associated with improved lubrication in vitro, hyaluronic acid viscosity and clinical efficacy are uncorrelated. This may be because traditional viscosity measurements capture only bulk viscosity, while on cartilage, hyaluronic acid is localized at the surface forming a highly viscous boundary layer. Our results demonstrate that functionalizing rheometer fixtures with cartilage surfaces significantly increases the effective viscosity of hyaluronic solutions (Chapter 4). This modification allows the localization of hyaluronic acid on cartilage to be captured in a commercial rheometer, thus providing a viscosity measurement that is more relevant to lubrication and therefore likely more predictive of clinical efficacy. Altogether, the studies in the following thesis unveil molecular interactions that occur during joint lubrication and examine their measurable macroscale effects in order to inform the development of improved therapeutic strategies for joint disease. The results emphasize the critical importance of interactions between synovial fluid molecules and the substrate they lubricate (either cartilage, or joint implant materials) on lubrication and wear protection mechanisms.