The study investigates the role of apoptosis signal-regulating kinase 1 (ASK1) in sustained activations of JNK and p38 MAP kinases and apoptosis. ASK1 is activated by various cytotoxic stresses, including TNF, Fas, and reactive oxygen species (ROS), and activates JNK and p38. The authors generated ASK1−/− mice to determine the function of ASK1 in apoptosis. They found that ASK1−/− embryonic fibroblasts (MEFs) lack sustained activations of JNK and p38 in response to TNF and H2O2, and are resistant to TNF- and H2O2-induced apoptosis. TNF-induced apoptosis requires ROS-dependent activation of ASK1–JNK/p38 pathways, while Fas-induced apoptosis does not. These findings indicate that ASK1 is selectively required for TNF- and oxidative stress-induced sustained activations of JNK/p38 and apoptosis.The study investigates the role of apoptosis signal-regulating kinase 1 (ASK1) in sustained activations of JNK and p38 MAP kinases and apoptosis. ASK1 is activated by various cytotoxic stresses, including TNF, Fas, and reactive oxygen species (ROS), and activates JNK and p38. The authors generated ASK1−/− mice to determine the function of ASK1 in apoptosis. They found that ASK1−/− embryonic fibroblasts (MEFs) lack sustained activations of JNK and p38 in response to TNF and H2O2, and are resistant to TNF- and H2O2-induced apoptosis. TNF-induced apoptosis requires ROS-dependent activation of ASK1–JNK/p38 pathways, while Fas-induced apoptosis does not. These findings indicate that ASK1 is selectively required for TNF- and oxidative stress-induced sustained activations of JNK/p38 and apoptosis.