Orthobiologic agents, including platelet-rich plasma, connective tissue progenitor cells derived from bone marrow, adipose, and other tissues, and purified cytokines and small peptides, have tremendous potential to target deficiencies in soft-tissue healing. The principal limitation currently is the variability in the composition and biologic activity of orthobiologic formulations, making it difficult to choose the optimal treatment for a specific tissue or pathology. Current data suggest that orthobiologics are "symptom-modifying," but there is little evidence that they can lead to true tissue regeneration ("structure-modifying"). A critically important need at this time is to identify sentinel markers of potency and biologic activity for different orthobiologic formulations so that we can match the treatment to the desired biologic effect for a specific tissue or pathology. Improved understanding of the underlying cellular and molecular mechanisms of tissue degeneration and repair will allow a precision medicine approach where we can choose the optimal orthobiologic treatment of specific orthopaedic problems. It is important for the clinician to be aware of the evolving regulatory status of orthobiologic treatments. Emerging therapies such as the use of exosomes and gene therapy approaches hold great promise as improved methods to both treat symptoms and affect tissue regeneration.