Articular cartilage is one of the most remarkable load bearing materials found in nature. Its unique composition provides some of the lowest friction coefficients ever measured and allows nearly frictionless articulation of our bodies’ joints. However, the breakdown and degeneration of cartilage in osteoarthritis is one of the leading causes of severe disability in the industrialized world, and no effective disease-modifying treatments are currently available. With this in mind, fully understanding how the mechanisms of cartilage lubrication change between health and disease can provide insight to develop new injectable materials targeted at lowering friction and restoring proper joint function. Despite the critical role of lubrication to joint health, evaluation of synovial fluid lubrication in disease on the acute timescale is limited. Specifically, it is unclear how temporal alterations in the critical synovial fluid lubricants, lubricin and hyaluronic acid (HA), affect the lubricating properties of pathological synovial fluid. Therefore, the overarching goal of this dissertation is to characterize the tribological properties of pathological synovial fluids and new materials to be used as lubrication therapies for cartilage. In this dissertation, Chapter 1 reviews the biologic and mechanical effects of commercially available HA viscosupplements. Chapter 2 uses the Stribeck framework to show that inflamed synovial fluid exhibits changes in friction modes and effective lubricating viscosities in a temporal manner, highlighting a critical time window where viscosupplements could be most beneficial in lowering friction. Chapters 3, 4, and 5 reveal that synthetic materials can effectively lubricate healthy and osteoarthritic cartilage. Chapter 4 further elucidates how injectable materials are not evenly distributed inside a joint after administration, and that the mechanical outcomes of these therapies is strongly linked to the ability of the material to localize to the cartilage surfaces inside a joint. Collectively these findings inform the design of a new class of viscosupplements and therapeutics to treat mild to moderate OA.