EFNB1 (ephrin B1) is a cell surface transmembrane ligand for Eph receptor tyrosine kinases that mediates contact-dependent bidirectional signaling between adjacent cells. It plays critical roles in neuronal, vascular, and epithelial development through axon guidance and cell-cell adhesion. EFNB1 shows high affinity for EPHB1, EPHB2, and EPHB3 receptors. In disease contexts, EFNB1 emerges as a key player in cancer progression. Tumor cells release EFNB1-containing exosomes that promote tumor innervation and axonogenesis 1. In esophageal squamous-cell carcinoma, aberrant EFNB1-EPHB4 interaction drives epithelial-mesenchymal transition and proliferation through SRC/ERK/AKT signaling, triggered by TP53 mutations causing ΔNP63 overexpression 2. In pancreatic ductal adenocarcinoma, reciprocal tumor-platelet interaction through the EPHB1-EFNB1 axis promotes liver metastatic outgrowth 3. EFNB1 also contributes to intestinal homeostasis: EFNB1-EPHB2 signaling regulates autophagy in colonic epithelial cells, and ephrin-B1-Fc recombinant protein alleviates dextran sodium sulfate-induced colitis in mice 4. Additionally, EFNB1 and EFNB2 expression on T cells correlates with rheumatoid arthritis disease activity and severity 5. Gene fusions involving EFNB1 have been detected in triple wild-type melanomas, with potential therapeutic implications 6.