To determine the physiological processes in which the transcription factor c-Rel may act, we have examined its pattern of expression in the avian embryo by in situ hybridization. These studies showed that c-rel is expressed ubiquitously at low levels and at high levels in isolated cells undergoing programmed cell death by apoptosis or autophagocytosis. To further establish a functional link between expression of c-rel and cell death, we examined the biological consequences of c-rel overexpression in vitro. In primary avian fibroblasts, overexpression of c-rel leads to transformation and dramatic life span extension. In contrast, bone marrow cells expressing high levels of c-rel undergo a process of programmed cell death displaying features of both apoptosis and autophagocytic cell death. Thus, these experiments suggest a critical role for c-rel not only in the control of cell proliferation, but also in the induction of cell death.