Orthobiologics—tissues and natural substances used to heal musculoskeletal pathologies—have seen a substantial rise in clinical application and research in the last decade. These agents have been employed for surgical and nonsurgical management of rotator cuff injuries, labral tears, and glenohumeral arthritis with the goal of augmenting innate healing responses. However, significant unknowns of efficacy and mechanisms of healing remain. Emerging evidence highlights variable outcomes which have been attributed to the type, preparation, and delivery method of orthobiologics. Additionally, regulatory challenges and the lack of standardized protocols contribute to inconsistencies in clinical practice. Treating physicians should be aware of current orthobiologic options including platelet-rich plasma (PRP), hyaluronic acid (HA), and bone marrow aspirates (BMA) as well as their reported clinical outcomes and limitations. Continuing research is critical for the development of evidence-based guidelines for orthobiologic treatments of the shoulder.