Eph receptors, the largest subfamily of receptor tyrosine kinases (RTKs), and their ephrin ligands are important mediators of cellcell communication regulating cell attachment, shape, and mobility of neuronal and endothelial cells in central nervous system function and in development.  Eph receptors can be divided into two subgroups: EphA and EphB. In mammals, the EphA class consists of eight members (EphA 1-7 and 10) that in general bind to ephrin-A members linked to the cell membrane through a glycosylphosphatidylinositol linkage. The EphB class consists of six members (EphB 1-6) that in general bind ephrin-B members that transverse the cell membrane. The Ephrin / EPH signaling pathway networks with the WNT signaling pathway during embryogenesis, tissue regeneration, and carcinogenesis. Recent studies show that Eph/EFN might be relevant in normal B-cell biology and could represent new potential prognostic markers and therapeutic targets for CLL.