Donors with nonspecific reactivity in viral screening or confirmatory assays are problematic for blood services because of donor management issues and product loss. Considerable experience has now accumulated in the use of screening and confirmatory assays; therefore, it is timely to examine the ways in which donors with nonspecific reactivity are managed. In this review, we summarize the causes and characteristics of nonspecific reactivity in blood donors and approaches for reducing the number of nonspecific reactive results and we offer some suggestions for improving the management of these donors.