Stem/progenitor cells contribute to normal development of organs, but their mutation may lead to many human diseases including cancer. Stem/progenitor cells and some of the cancer cells have the same abilities of self-renewal and differentiation, suggesting that tumors were initiated from mutated stem/progenitor cells, the cancer stem/progenitor cells. The recent studies on the origin of the non-Hodgkin's lymphomas has proved that the second-hit aggravates gene mutation in lymphocytic progenitor cells, leading to the generation of lymphoma. This review summarizes the current advances in the studies of the second-hit at stem/progenitor cells in oncogenesis of B-cell non-Hodgkin's lymphoma.