Natural killer (NK) cells serve as a first line of defense against acute viral infections. Immunogenetic association data suggest that NK cells also influence the course of chronic viral infections, such as infections with HIV-1 and hepatitis C virus (HCV). Chronic stages of these infections have a negative impact on NK cell function and promote the appearance of phenotypically and functionally abnormal NK cells. In this paper, we summarize available data on CD56^neg NK cells, an aberrant NK cell subset found in small numbers in healthy individuals and at elevated levels in individuals chronically infected with HIV-1 and HCV. We discuss current knowledge of CD56^neg NK cells, with a particular emphasis on their accumulation during chronic infection and the possible consequences of this for the host.