AbstractImmune memory is well known as a signature of the adaptive immune system. Recently, enhanced responses to subsequent triggers are also observed in innate immune system, termed trained immunity (TI). Awakening of innate immune memory is required for host defense, such as anti‐pathogen and anti‐tumor responses. However, hyper‐reactivation of trained innate immune cells also gives rise to undesirable inflammation. Mucosa immune system serves as the first defense line against pathogens. Trained immunity of mucosal immune system is tightly associated with the outcomes of mucosal diseases. In this review, we discuss the role of trained immunity in mucosal‐associated diseases and the underlying mechanisms. We summarize the metabolic and epigenetic changes of trained immune cells and highlight their potential in clinical treatment.This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology