The threat from cancer cells is inherently linked to cell-cycle progression, and viral genomes commonly replicate, for example, within episomes or proviruses, during mitosis. We report here that human natural killer (NK) cells bound cells in mitosis and attacked pathogenic cells in mitosis more effectively than the same cells in other stages of the cell cycle. Thus, cells in mitosis warrant and undergo heightened surveillance, a novel strategy for immunologic assessment of danger. Recognition of cells in mitosis involved ligation of activating NK-cell receptors and binding to target-cell hyaluronan, a component of the pericellular matrix known to be increased during mitosis. Direct interaction between activating NK-cell receptors and hyaluronan is possible, but other mechanisms consistent with our data are also discussed.