CX3CR1 is a chemokine receptor with a single ligand, the membrane-tethered che- mokine CX3CL1 (fractalkine). All blood monocytes express CX3CR1, but its lev- els differ between the main 2 subsets, with human CD16+ and murine Gr1lowmonocytes being CX3CR1hi. Here, we re- port that absence of either CX3CR1 or CX3CL1 results in a significant reduction of Gr1low blood monocyte levels under both steady-state and inflammatory con- ditions. Introduction of a Bc12 transgene restored the wild-type phenotype, sug- gesting that the CX3C axis provides an essential survival signal. Supporting this notion, we show that CX3CL1 specifically rescues cultured human monocytes from induced cell death. Human CX3CR1 gene polymorphisms are risk factors for athero- sclerosis and mice deficient for the CX3C receptor or ligand are relatively protected from atherosclerosis development. How- ever, the mechanistic role of CX3CR1 in atherogenesis remains unclear. Here, we show that enforced survival of mono- cytes and plaque-resident phagocytes, including foam cells, restored atherogen- esis in CX3CR1-deficent mice. The fact that CX3CL1-CX3CR1 interactions confer an essential survival signal, whose ab- sence leads to increased death of mono- cytes and/or foam cells, might provide a mechanistic explanation for the role of the CX 3C chemokine family in atherogen- esis.