Periarticular tissues have traditionally been regarded as a collection of discrete peri-articular structures surrounding the joint – tendons, ligaments, joint capsule, fasciae, synovial bursae, entheses and muscles. Emerging evidence indicates that in chronic pathology these structures function as a unified neurovascular–connective tissue “organ”, in which mechanical injury, disturbed innervation, impaired vascular regulation and persistent inflammation, including infection-associated inflammation, converge into a common pathogenetic trajectory leading to enthesopathy. This review summarizes current data on the structure and pathophysiology of periarticular tissues, the role of the peripheral nervous system and the microvascular bed, as well as the contribution of infectious triggers to the development of the pathological process. We discuss the concept of a pathogenetic cascade: “mechanical loading – neural dysregulation – vascular remodelling and pathological angiogenesis – infection-driven and autoimmune inflammation – chronicity and structural remodelling of the enthesis organ”. Particular attention is paid to clinical and imaging features of lesions of the synovio-entheseal complex and their relationship to cellular, structural and metabolic disturbances. Potential therapeutic targets in enthesopathy are outlined, including modulation of angiogenesis, neurovascular complexes and immune pathways. The proposed model provides a framework for unifying approaches to diagnosis and treatment of periarticular pathology.