Tenosynovial giant cell tumor (TGCT) is a rare benign tumor that involves the 
synovium, bursa, and tendon sheath, resulting in reduced mobility of the 
affected joint or limb. The current standard of care for TGCT is surgical 
resection. However, some patients have tumor recurrence, present with 
unresectable tumors, or have tumors that are in locations where resection could 
result in amputations or significant debility. Therefore, the development of 
systemic agents with activity against TGCT to expand treatment options is a 
highly unmet medical need. Pathologically, TGCT is characterized by the 
overexpression of colony﻿-stimulating factor 1 (CSF-1), which leads to the 
recruitment of colony﻿-stimulating factor-1 receptor (CSF-1R) expressing 
macrophages that make up the primary cell type within these giant cell tumors. 
The binding of CSF-1 and CSF-1R controls cell survival and proliferation of 
monocytes and the switch from a monocytic to macrophage phenotype contributing 
to the growth and inflammation within these tumors. Therefore, molecules that 
target CSF-1/CSF-1R have emerged as potential systemic agents for the treatment 
of TGCT. Given the role of macrophages in regulating tumorigenesis, 
CSF1/CSF1R-targeting agents have emerged as attractive therapeutic targets for 
solid tumors. Pexidartinib is an orally bioavailable and potent inhibitor of 
CSF-1R which is one of the most clinically used agents. In this review, we 
discuss the biology of TGCT and review the pre-clinical and clinical development 
of pexidartinib which ultimately led to the FDA approval of this agent for the 
treatment of TGCT as well as ongoing clinical studies utilizing pexidartinib in 
the setting of cancer.