Rotator cuff pathology is a significant cause of shoulder pain. Operative repair of rotator cuff is an established standard of care for these patient, however, failure of the procedure is common. Systemic conditions such as diabetes mellitus, hypocholesteremia, thyroid disease, and smoking significantly affect the outcomes of rotator cuff repair and have significant implications for the management of these patients. Diabetes mellitus has been proposed to damage tendons through nonenzymatic glycosylation of collagen with advanced glycation end-product formation and impaired microcirculation. Hypocholesteremia may lead to fatty infiltration and subsequent proinflammatory degenerative enzymatic degeneration. Thyroid disease may disrupt tendon homeostasis through the alteration of collagen production and the accumulation of glycosaminoglycans. Lastly, smoking inhibits tendon healing through the induction of hypovascularity and hypoperfusion. Understanding of the implications these systemic conditions have on the outcomes is important in the management of rotator cuff disease.