Natural killer (NK) cells are large granular lymphocytes that play an important role in the defense against virally infected or malignant cells (1). Their activity can be characterized as nonadaptive and independent of MHC restriction (1, 2). A variety of NK cell functions including cytotoxicity, proliferation, chemotaxis, and cytokine production are modulated by regulatory cytokines including IFN-αβ, IL-2, IL-12, IL-18, IL-10, and TNF (reviewed in Refs. 3 and 4). Because cytokines induce such a broad range of effects in NK cells, the potential for alterations in gene expression in stimulated cells is very great. To determine which genes are regulated in response to cytokine stimulation, our laboratory has used cDNA microarray technology to examine gene expression in NK cells. Microarray technology is very useful because it allows for large-scale examination of gene expression. Additionally, this technology has proved useful in identifying physiologically relevant gene expression patterns in eukaryotic systems such as yeast (5) and fibroblasts (6) as well as predicting patterns of gene expression in tumor cells (7, 8). To examine gene expression in response to cytokine stimulation, a human NK cell line, NK92, was stimulated with IL-2 alone or in combination with IL-12 or IL-18. These cytokines were chosen because of their ability to induce NK cell responses; however, little is known about the repertoire of genes that are activated by these cytokines. Microarray analysis of gene expression in NK92 cells identified a variety of genes whose mRNA expression patterns change in response to cytokine stimulation. The genes encoding the mRNAs are not specific to any one pathway; however, changes in cytokine, chemokine, and chemokine receptor gene mRNAs were prevalent. Our mRNA studies on chemokine receptor gene expression were extended to cell surface analysis of receptor densities in cytokine-treated primary NK cells. Using FACS analysis, we observed a significant decrease in CXCR3 receptor expression in NK cells treated for 24 h with IL-2 and IL-12 alone or in combination. Recently, alterations in chemokine receptor expression were reported in IL-2-stimulated NK cells (9); however, the cells were cultured in IL-2 for 8–10 days. In contrast, our data demonstrate that cytokines can modify chemokine receptor function within hours, thus supporting a model whereby cytokines, in particular IL-2 and IL-12, regulate chemokine receptor expression in a direct, rapid, and novel manner.