Platelet-rich plasma (PRP) has emerged as a central focus in regenerative medicine due to its potential to enhance tissue healing in a variety of musculoskeletal conditions. The PRP is derived from the patient’s own blood and delivers a supraphysiological concentration of platelets that is rich in growth factors. As interest in orthobiologics grows, particularly in the context of orthopedics and sports medicine, understanding the scientific basis, preparation methods, and clinical implications of PRP is essential for informed and effective use. Despite encouraging experimental data and increasing adoption in clinical practice, outcomes have been inconsistent—largely due to variability in PRP formulations, lack of standardized classification systems, and unclear protocols for preparation and administration. This chapter introduces the foundational principles behind PRP and provides a practical framework for clinicians by exploring the mechanisms of action, key factors affecting its efficacy, and current evidence in support of its use. The chapter aims to bridge the gap between laboratory research and clinical application, guiding more personalized and evidence-based approaches to PRP therapy for treating cartilage lesions, tendinopathies, muscle injuries, ligament injuries, meniscal lesions, and bone healing. Ultimately, PRP shows promise as a safe, minimally invasive regenerative therapy, but its routine use should be guided by high-level clinical evidence and personalized to each patient’s condition.