Rotator cuff tears are common, and lead to shoulder pain and functional impairment. Despite their frequency and related disability, etiology and pathogenesis are still debated. Multiple factors contribute to tears of the rotator cuff. Extrinsic factors are anatomic variables, such as acromial morphologic characteristics, os acromiale, and acromial spurs that compress the rotator cuff by bony impingement or direct pressure from the surrounding soft tissue. Intrinsic factors arise from the tendon itself, because of tensile overload, aging, microvascular supply, traumatisms, or degeneration. Little information is available from a cellular and molecular point of view. We reviewed the biological factors involved in the pathogenesis of rotator cuff tears. Understanding the mechanism of rotator cuff pathology would facilitate the rationale for therapeutic interventions, by guiding the design, selection, and implementation of treatment strategies such as biologic modulation and preventive measures.