Introduction <p>Peptides occupy a strategic position between small molecules and biologics, offering high target specificity, favourable safety profiles, and chemical tractability. In musculoskeletal medicine, they address diverse pathological processes—including inflammation, degeneration, infection, oncology, and fibrosis—through mechanisms that conventional therapeutics cannot replicate. Two principal frameworks underpin this field. Throughout this review, we differentiate bioactive peptides, defined as naturally occurring or food-derived sequences that exert physiological effects, from therapeutic peptides, which are purposefully engineered pharmaceutical agents intended for clinical application. Although conceptual and functional overlap exists, this distinction is important because the two categories are subject to different regulatory pathways and evidentiary requirements. Accordingly, peptides discussed in this review fall into two broad groups: first, bioactive peptides originating from food proteins, endogenous biological systems, or laboratory synthesis, typically comprising 2– 50 amino acids; and second, therapeutic peptides that are rationally designed to address traditional limitations of peptide-based agents, including proteolytic degradation and challenges related to stability, bioavailability, and delivery.</p> Methods <p>This narrative review synthesizes perspectives from both bioactive and engineered peptide classes across musculoskeletal medicine. The narrative format was selected to accommodate heterogeneous evidence spanning preclinical mechanisms, clinical trials, and translational barriers where systematic synthesis would be inappropriate. The review maps engineering solutions to tissue-specific delivery challenges, critically appraises evidence across primary musculoskeletal indications, and identifies translational bottlenecks separating preclinical claims from clinical reality. The analysis integrates mechanistic plausibility, clinical trial data, and regulatory milestones to evaluate the maturity of peptide-based interventions.</p> Results <p>A recurrent pattern emerges: while mechanistic plausibility remains strong across peptide classes, clinical maturity varies significantly. Collagen peptides and glucagon-like peptide-1 (GLP-1) analogues demonstrate robust clinical translation, with regulatory approval validating their therapeutic relevance. In contrast, many regenerative and anti-infective peptide candidates remain predominantly in preclinical stages, despite compelling mechanistic data. This heterogeneity underscores the uneven trajectory of peptide therapeutics within musculoskeletal medicine.</p> Conclusion <p>Peptides represent a promising molecular class with unique advantages over conventional therapeutics. However, the disparity between mechanistic promise and clinical maturity has direct implications for patient counselling, trial design, regulatory oversight, and ethical considerations surrounding the off-label and grey-market use of these therapies. Bridging this translational gap will require rigorous clinical validation, improved delivery strategies, and careful regulatory frameworks to ensure safe and effective integration of peptide therapeutics into musculoskeletal medicine.</p> Graphical Abstract <p></p>