Tenosynovial giant cell tumor is a non-malignant primary locally aggressive articular disease that affects the synovium of joints, tendon sheaths, and bursae. It is characterized by a translocation t (1
2), leading to the overexpression of CSF1 in the tumor microenvironment. CSF1 induces the recruitment of non-malignant cells, mainly macrophages, followed by the differentiation and polarization of these cells into the M2 phenotype. Surgery, particularly total synovectomy, remains the cornerstone of TGCT management. However, recurrence rates vary, reaching 40 to 60% in diffuse disease, often resulting in progressive joint dysfunction, pain, and potential need for joint replacement or limb amputation. Systemic therapy is recommended in recurrent TGCT in patients not amenable to additional surgery. Targeting the CSF1/CSF1R axis has successfully improved tumor responses and enhanced symptomatic function. In this review, we aim to explore contemporary paradigms in inoperable TGCT patients, with a focus on the physiopathology, clinical efficacy, and safety of CSF1 or CSF1R inhibitors.