Apoptosis is a critical early cellular event in the development of polycystickidney disease (PKD) in humans and mice. In the SBM transgenic model of PKD, both apoptosis and proliferation are c-myc driven and are independent of p53 and Bcl-2 pathways. On the basis of recent evidence implicating the FasL/Fas pathway in c-myc-induced apoptosis, we investigated the potential interaction of these pathways in vivo. We first evaluated the expression of FasL in renal tissues of SBM mice. This analysis showed that the level of FasL expression was elevated 3–4-fold in the SBM kidneys, indicating a potential autocrine suicidal mechanism. We next crossed the SBM mice with gld mice mutated in FasL. The progenies had comparable renal epithelial apoptotic and proliferation rates and a cystic phenotype in all SBM genotypes irrespective of the FasL genotype. Our study proves that c-myc-induced apoptosis can be independent of the FasL/Fas pathway in vivo and implicates the existence of a novel c-myc-driven apoptotic pathway.