During development, natural killer (NK) cells exit the BM to reach the blood. CXCR4 retains NK cells in the BM, whereas the sphingosine-1 phosphate receptor 5 (S1P5) promotes their exit from this organ. However, how the action of these receptors is coordinated to preserve NK-cell development in the BM parenchyma while providing mature NK cells at the periphery is unclear. The role of CXCR4 and S1P5 in NK-cell recirculation at the periphery is also unknown. In the present study, we show that, during NK-cell differentiation, CXCR4 expression decreases whereas S1P5 expression increases, thus favoring the exit of mature NK cells via BM sinusoids. Using S1P5(-/-) mice and a new knockin mouse model in which CXCR4 cannot be desensitized (a mouse model of warts, hypogammaglobulinemia, infections, and myelokathexis [WHIM] syndrome), we demonstrate that NK-cell exit from the BM requires both CXCR4 desensitization and S1P5 engagement. These 2 signals occur independently of each other: CXCR4 desensitization is not induced by S1P5 engagement and vice versa. Once in the blood, the S1P concentration increases and S1P5 responsiveness decreases. This responsiveness is recovered in the lymph nodes to allow NK-cell exit via lymphatics in a CXCR4-independent manner. Therefore, coordinated changes in CXCR4 and S1P5 responsiveness govern NK-cell trafficking.