The article reviews the emerging concept of trained immunity, a process where innate immune cells acquire antigen-agnostic memory and exhibit increased responsiveness to secondary stimulation. This long-term, de-facto innate immune memory, also known as trained immunity, is mediated through metabolic rewiring and epigenetic modifications. While trained immunity can provide advantages in countering immune paralysis, its overactivation contributes to autoinflammatory and autoimmune disorders. The review covers the latest advancements in innate immune memory, the mechanisms underlying trained immunity, and its implications for various diseases. It also explores the potential therapeutic targeting of trained immunity in immune-related disorders. The article highlights the evolutionary conservation of innate immune memory mechanisms and their role in vertebrates, as well as the non-specific protection induced by live attenuated vaccines like BCG. The mechanisms of epigenetic reprogramming and immunometabolic circuits in trained immunity are discussed, including the involvement of histone modifications, DNA methylation, and metabolic pathways such as aerobic glycolysis and the TCA cycle. The article further examines the cell populations that mediate trained immunity, including monocytes, macrophages, dendritic cells, natural killer (NK) cells, innate lymphoid cells, neutrophils, and microglia, as well as non-immune cells like epithelial and fibroblasts. Finally, it differentiates between central and peripheral trained immunity, emphasizing the role of bone marrow progenitor cells and tissue-resident macrophages in maintaining tissue function and protection against infections and inflammatory diseases.The article reviews the emerging concept of trained immunity, a process where innate immune cells acquire antigen-agnostic memory and exhibit increased responsiveness to secondary stimulation. This long-term, de-facto innate immune memory, also known as trained immunity, is mediated through metabolic rewiring and epigenetic modifications. While trained immunity can provide advantages in countering immune paralysis, its overactivation contributes to autoinflammatory and autoimmune disorders. The review covers the latest advancements in innate immune memory, the mechanisms underlying trained immunity, and its implications for various diseases. It also explores the potential therapeutic targeting of trained immunity in immune-related disorders. The article highlights the evolutionary conservation of innate immune memory mechanisms and their role in vertebrates, as well as the non-specific protection induced by live attenuated vaccines like BCG. The mechanisms of epigenetic reprogramming and immunometabolic circuits in trained immunity are discussed, including the involvement of histone modifications, DNA methylation, and metabolic pathways such as aerobic glycolysis and the TCA cycle. The article further examines the cell populations that mediate trained immunity, including monocytes, macrophages, dendritic cells, natural killer (NK) cells, innate lymphoid cells, neutrophils, and microglia, as well as non-immune cells like epithelial and fibroblasts. Finally, it differentiates between central and peripheral trained immunity, emphasizing the role of bone marrow progenitor cells and tissue-resident macrophages in maintaining tissue function and protection against infections and inflammatory diseases.