We report the finding of a large number of new common fragile sites. Thirty-one (56%) of 55 common fragile sites found in a sample of human lymphocytes were ones not described at the Eighth International Workshop on Human Gene Mapping (HGM 8). The sample consisted of 3023 lymphocytes from nine unrelated individuals with a history of genitourinary malignancy. The lymphocytes were challenged in culture with aphidicolin (Apc), fluorodeoxyuridine (FUdR), 5-azacytidine (Aza), and bromodeoxyuridine (BrdU). Thirteen of the new common fragile sites were induced by Apc and FUdR, nine by Aza, five by BrdU, and four by combined means. The sites induced by Apc and FUdR were cross-induced by BrdU. The fragile sites induced by a diminished concentration of Aza were largely located in heterochromatic regions and were cross-induced by BrdU and FUdR. Exposure to BrdU for 24 hours, a technique hitherto restricted to rare fragile sites, induced several common fragile sites. Control lymphocytes had far fewer gaps and breaks, but these were clustered predominantly at high-expression fragile sites. Because more than half of the common fragile sites in this study were new, it is clear that much remains to be learned. Because the classes of fragile sites reveal cross-induction, we propose that fragile sites share structures in DNA.