Sertoli cells, the supportive cells in the seminiferous epithelium, orchestrate spermatogenesis by providing structural and nutritional support to germ cells. In the rat, physiological apoptosis occurs continuously to limit the size of the germ cell population to numbers that can be adequately supported. This form of germ cell death is exaggerated after testicular insults such as toxicant treatment, radiation, and heat exposure. The Fas system has been proposed as a key regulator of the activation of germ cell apoptosis. According to this model, Fas ligand (FasL) and Fas, expressed by Sertoli cells and germ cells, respectively, respond to environmental conditions and initiate germ cell death. To assess the role of the Fas system in various testicular injury models, a semiquantitative RT-PCR technique was used to evaluate the expression kinetics of both FasL and Fas after induction of massive germ cell death. Radiation exposure, which targets actively dividing germ cells, produced an up-regulation of Fas gene expression, but not FasL gene expression. However, administration of mono-(2-ethylhexyl)phthalate and 2,5-hexanedione, two widely studied Sertoli cell toxicants, resulted in up-regulated expression of both FasL and Fas. These data support the following hypotheses: 1) up-regulation of Fas is a common and critical step for initiating germ cell death in vivo; and 2) if Sertoli cells are injured, Sertoli cells up-regulate FasL to eliminate Fas-positive germ cells, which cannot be supported adequately.