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Natural killer (NK) cells are a subset of innate immune lymphocytes that interrogate potential target cells and rapidly respond by lysing them or secreting inflammatory immunomodulators. Productive interactions between NK cells and targets such as tumor cells or virally infected cells are critical for immunological control of malignancies and infections. For individual NK cells, however, the relationship between the characteristics of these cell–cell interactions, cytolysis, and secretory activity is not well understood. Here, we used arrays of subnanoliter wells (nanowells) to monitor individual NK cell–target cell interactions and quantify the resulting cytolytic and secretory responses. We show that NK cells operate independently when lysing a single target cell and that lysis is most probable during an NK cell's first encounter with a target. Furthermore, we demonstrate that the secretion of interferon-γ (IFN-γ) occurs most often among NK cells that become the least motile upon contacting a target cell but is largely independent of cytolysis. Our findings demonstrate that integrated analysis of the cell–cell interaction parameters, cytolytic activity, and secretory activity of single NK cells can reveal new insights into how these complex functions are related within individual cells., Charles A. Dana Foundation, W. M. Keck Foundation, Ragon Institute of MGH, MIT and Harvard, National Science Foundation (U.S.) (Fellowship), Massachusetts Institute of Technology (Collamore-Rogers Fellowship)