Mihai G. Netea

Summary Over the past decade, compelling evidence has unveiled previously overlooked adaptive characteristics of innate immune cells. Beyond their traditional role in providing short, non‐specific protection against pathogens, innate immune cells can acquire antigen‐agnostic memory, exhibiting increased responsiveness to secondary stimulation. This long‐term de‐facto innate immune memory, also termed trained immunity , is mediated through extensive metabolic rewiring and epigenetic modifications. While the upregulation of trained immunity proves advantageous in countering immune paralysis, its overactivation contributes to the pathogenesis of autoinflammatory and autoimmune disorders. In this review, we present the latest advancements in the field of innate immune memory followed by a description of the fundamental mechanisms underpinning trained immunity generation and different cell types that mediate it. Furthermore, we explore its implications for various diseases and examine current limitations and its potential therapeutic targeting in immune‐related disorders.