Purpose of Review <p>Fatty infiltration (FI) of the rotator cuff is a critical determinant of clinical outcomes following rotator cuff injuries and repairs. This review examines the natural history, pathophysiology, imaging evaluation, and treatment strategies for FI, highlighting recent insights into its cellular mechanisms and emerging therapeutic approaches.</p> Recent Findings <p>Animal models demonstrate that FI begins shortly after tendon injury, progresses with muscle retraction and denervation, and is largely irreversible despite repair. Key cellular drivers include fibroadipogenic progenitor cells (FAPs), influenced by mechanical loading and inflammatory signaling pathways. Clinical studies show that FI is associated with advanced age, female sex, and full-thickness tears. Higher degrees of preoperative FI correlate with poorer functional outcomes and increased re-tear rates. Novel therapeutic targets, including pathways regulating FAP activity, TGF-β, and cell-based therapies, show promise in preclinical studies. Emerging strategies such as leukocyte-poor platelet-rich plasma (PRP) may mitigate FI progression in clinical settings.</p> Summary <p>Fatty infiltration remains a significant barrier to successful rotator cuff repair and functional recovery. While surgical repair may slow FI progression, it is not consistently effective in reversing established muscle degeneration. Improved understanding of the molecular mechanisms driving FI has identified potential therapeutic targets, but their clinical applicability requires further validation. Future advances in regenerative medicine, including cell-based therapies and modulation of fibroadipogenic progenitors, offer hope for mitigating FI and improving long-term outcomes.</p>