RASAL3 is a RAS GTPase-activating protein (RasGAP) that negatively regulates RAS/ERK signaling and plays critical roles in immune cell development and migration. 1 In hematopoietic cells, RASAL3 is predominantly expressed in NKT, B, and T cells, where it restricts Ras activity to enable proper NKT cell expansion in the liver; RASAL3-deficient mice show severe NKT cell depletion with impaired cytokine production. 1 Beyond immunity, RASAL3 localizes to the plasma membrane and cytoplasm where it modulates cell motility through context-dependent effects on RAS signaling. 2 Recruitment of RASAL3 to the cell front suppresses protrusions and redirects migration, while rear localization enhances polarization and directional movement via myosin II and mTORC2-dependent mechanisms. 3 RASAL3 also functions within the CCDC88B/ARHGEF2 complex to regulate dendritic cell migration in neuroinflammation and colitis by modulating RHOA activation. 4 Clinically, RASAL3 is epigenetically silenced in prostate cancer-associated fibroblasts, promoting oncogenic RAS activity that drives glutamine metabolism and therapy resistance. 5 In lung adenocarcinoma, high RASAL3 expression correlates with improved survival and enhanced CD8+ T cell infiltration. 6 RASAL3 dysregulation associates with diverticulitis pathogenesis, suggesting broader roles in inflammatory disease.