Within the chemokine family of small chemotactic polypeptides CX3CL1 (fractalkine) and CXCL16 (SR-PSOX) are exceptional in that they are synthesized as transmembrane molecules and can be cleaved from the cell surface to produce a soluble chemoattractant. As transmembrane molecules on the surface of endothelial cells, CX3CL1 and CXCL16 can interact with their receptors CX3CR1 and CXCR6, respectively, which are expressed on leukocyte subtypes. This interaction leads to cell-cell adhesion that is resistant to shear forces. Transmembrane CX3CL1 and CXCL16 are constitutively shed from the cell surface by the activity of a disintegrin and metalloproteinase (ADAM) 10, and cleavage can be rapidly enhanced by activation of the closely related enzyme ADAM17. This cleavage leads to the downregulation of adhesive properties and may even result in the detachment of bound cells. Functionally, both chemokines appear to exert homeostatic and inflammatory activities. Basal expression of CX3CL1 or CXCL16 may be relevant for positioning and survival of tissue-homing leukocytes. Upregulated expression is found under inflammatory conditions such as atherosclerosis where CXCL16 may have a dual function by acting as an adhesion molecule and by promoting uptake of oxidized LDL as a scavenger receptor. Accumulating evidence from knockout mice and genetic polymorphisms in humans points towards a differential contribution of CX3CL1 and CXCL16 in atherosclerosis, where shedding may serve to further regulate their biological functions. Small molecules that block either the receptors or the shedding enzymes of transmembrane chemokines need to be tested in animal models of vascular inflammation.