B-1 cells play critical roles in defending against microbial invasion and in housekeeping removal of cellular debris. B-1 cells secrete natural antibody and manifest functions that influence T cell expansion and differentiation and in these and other ways differ from conventional B-2 cells. B-1 cells were originally studied in mice where they are easily distinguished from B-2 cells, but their identity in the human system remained poorly defined for many years. Recently, functional criteria for human B-1 cells were established on the basis of murine findings, and reverse engineering resulted in identification of the phenotypic profile, CD20+CD27+CD43+CD70−, for B-1 cells found in both umbilical cord blood and adult peripheral blood. Human B-1 cells may contribute to multiple disease states through production of autoantibody and stimulation/modulation of T cell activity. Human B-1 cells could be a rich source of antibodies useful in treating diseases present in elderly populations where natural antibody protection may have eroded. Manipulation of human B-1 cell numbers and/or activity may be a new avenue for altering T cell function and treating immune dyscrasias.