CX(3)CL1, or fractalkine, the unique member of the CX(3)C chemokine family, exists as a transmembrane glycoprotein, as well as in soluble form, each mediating different biological activities, and is constitutively expressed in many hematopoietic and nonhematopoietic tissues. CX(3)CR1, the CX(3)CL1 exclusive receptor, is a classical GPCR, expressed on NK cells, CD14(+) monocytes, and some subpopulation of T cells, B cells, and mast cells. A recent paper by our group has demonstrated for the first time that highly purified human B cells from tonsil and peripheral blood expressed CX(3)CR1 at mRNA and protein levels. In particular, tonsil naïve, GC, and memory B cells expressed CX(3)CR1, but only GC centrocytes were attracted by soluble CX(3)CL1, which with its receptor, are also involved in the pathogenesis of several inflammatory disorders, as well as of cancer. Previous studies have shown that CX(3)CR1 is up-regulated in different types of B cell lymphoma, as well as in B-CLL. Recently, we have demonstrated that the CX(3)CL1/CX(3)CR1 axis is involved in the interaction of B-CLL cells with their microenvironment. Taken together, our data delineate a novel role for the CX(3)CL1/CX(3)CR1 complex in the biology of normal B cells and B-CLL cells. These topics are the subject of this review article.