Platelet-rich plasma (PRP) is a non-standardized autologous blood product that has been used for around 20 years in musculoskeletal pathology, initially by orthopedic surgeons and then by other locomotor specialists. Despite its growing use and numerous studies, benefit is controversial. Intra-articular injection in knee osteoarthritis were recently recommended by a few scientific societies and research groups, based on consensus. Tendinopathies and traumatic muscle pathology are still not covered by guidelines. In orthopedics, PRP and its derivative, platelet-rich fibrin (PRF), or bone marrow concentrates are used in non-union, aseptic osteonecrosis, in arthroscopic surgery, and pediatric orthopedics. Methodological difficulties related to variations in PRP quality and multiple biases explain the low level of evidence in controlled trials and meta-analyses, which do not always have the desired rigor. However, the experimental data are convincing, and biology is advancing rapidly to explain the mode of action of PRP, a complex biological system that acts as a buffer, restoring homeostasis and stimulating deficient tissue repair. After discussing the levels of evidence and the difficulties of phenotyping, the contraindications and adverse effects, rarely discussed in the literature, are presented. Solutions are proposed to advance knowledge and evidence for this treatment, which has the advantage of being more natural, without iatrogenic or adverse effects, but which must comply with rules of good practice and avoid abuses. PRP injections must be integrated into a comprehensive treatment plan with non-pharmacological measures and post-procedural care that needs to be better defined. The future likely lies in using different types of PRP depending on the pathology and the patient, probably combined with other orthobiotherapies, for more efficient personalized medicine.