Gastrointestinal stromal tumor (GIST) represents a paradigm for clinically 
effective targeted inhibition of oncogenic driver mutations in cancer. Five 
drugs are currently positioned as the standard of care for the treatment of 
advanced or metastatic GIST patients. This is the result of continuous, deep 
understanding of KIT and PDGFRA GIST oncogenic drivers as well as the resistance 
mechanisms associated to tumor progression. However, the complexity of GIST 
molecular heterogeneity is an evolving field, and critical questions remain 
open. Specifically, the clinical benefit of approved and/or investigated 
targeted agents is strikingly modest at advanced stages of the disease when 
compared with the activity of first-line imatinib. Ripretinib is a novel 
switch-pocket inhibitor with broad activity against KIT and PDGFRA oncoproteins 
and has recently demonstrated antitumoral activity across phase I to phase III 
clinical trials. Therefore, ripretinib has emerged as a new standard of care for 
advanced, multi-resistant GIST patients. Based on this data, the Food and Drug 
Administration has granted in 2020 the approval of ripretinib for GIST patients 
after progression to imatinib, sunitinib and regorafenib. This, in turn, 
constitutes a major breakthrough in sarcoma drug development, as there have not 
been new treatment approvals in GIST for nearly a decade. Herein, we provide a 
critical review on the preclinical and clinical development of ripretinib in 
GIST. Furthermore, we seek to assess the biological and clinical impact of this 
new standard of care on the course of the disease, aiming to provide an insight 
on future treatments strategies for the next coming years.