Cells are always exposed to various types of stress, including physical, chemical, and biological stresses, and are required to sense immediately and respond appropriately to these stresses. The apoptosis signal-regulating kinase (ASK) family members are stress-responsive kinases, which are activated by not only physicochemical stresses, such as oxidative stress, osmotic pressure, calcium overload, and anti-cancer drugs, but also biological stresses, such as inflammatory cytokines and pathogen infection. Recently, we found that ASK1, a member of ASK family, is activated by bacterial components, such as lipopolysaccharide, in a reactive oxygen species (ROS)-dependent manner, demonstrating that ASK1 is required for the innate immune response and plays a critical role in the regulation of innate immune signaling. Moreover, our findings indicate that ROS are common mediators in physicochemical stress signaling, including redox signaling, and biological stress signaling, including innate immune signaling. This review especially focuses on the roles of ASK family in innate immunity and provides recent progress in our knowledge on activation mechanisms and physiological functions of ASK family kinases in innate immune responses.