Living organisms are continuously exposed to pathogens such as viruses and bacteria. Soon after a limited number of germline-encoded receptors, called pathogen recognition receptors, sense pathogen-associated molecular patterns, hosts trigger innate immune responses, including production of type Ⅰ interferons, proinflammatory cytokines, and cellular apoptosis, to limit propagation of invading pathogens. Importantly, these host responses are also activated during inflammatory diseases, irrespective of pathogen infection, and often play a causal role in pathogenesis and progression of these diseases, thereby implying an intimate link between immune responses and inflammatory disease. The apoptosis signal-regulating kinase (ASK) family belongs to the larger MAP3K family that controls various stress responses. Here, I summarize the critical roles of members of the ASK family during infection and inflammatory disease, and discuss the relationship between these two noxious conditions.