The maintenance of joint health relies on a complex interplay of biological factors and tissue structures within the joint microenvironment. Disruptions in this balance, such as those caused by injury or aging, can lead to chronic conditions like osteoarthritis (OA). Emerging orthobiologic therapies, including platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC), aim to enhance the body’s intrinsic healing mechanisms. However, the variability in these therapies’ composition and the presence of both beneficial and detrimental bioactive molecules create challenges in achieving consistent therapeutic outcomes. Recent advancements in extracellular vesicles (EVs) research highlight their role in cellular communication and tissue repair, though their therapeutic potential may be limited by the presence of deleterious factors. This chapter looks into the mechanisms behind joint health maintenance, the challenges of current orthobiologic therapies, and explores future directions aimed at optimizing these treatments through advanced research in extracellular vesicles, senolytics, and anti-fibrotic agents to enhance therapeutic outcomes in complex joints.