Gut-associated lymphoid tissues (GALT) are chronically activated by the intestinal microbiota, maintaining gut homeostasis and supporting immune responses. GALT differs from other lymphoid tissues in several ways, including its ability to propagate IgA responses against glycans and support the development of systemic B cells in certain species, such as humans. GALT is organized lymphoid tissue distributed along the gastrointestinal tract, with Peyer's patches being the most abundant in the terminal ileum. It lacks a capsule and afferent lymphatics, and its structure includes the follicle-associated epithelium (FAE), which contains antigen-sampling microfollicular (M) cells. GALT supports the maturation and propagation of B cells, including the development of marginal zone B (MZB) cells, which mediate rapid systemic immunity to T-cell-independent (TI) antigens. Recent advances in technologies, such as single-cell transcriptomics and imaging mass cytometry, have enhanced our understanding of GALT's unique features and its interactions with the microbiota. GALT's chronic activation by the microbiota leads to the formation of germinal centers (GCs), where B cells undergo affinity maturation and selection. In humans, GALT supports the development of innate-like MZB cells that circulate in the blood and reside in the spleen, contributing to protective immunity in the lungs. The presence of TI antigens from the gut microbiota and pre-existing GCs in GALT creates a unique environment where B cells can both mutate their V regions and be selected for higher affinities. GALT also plays a role in the maturation of MZB cells, which acquire specificity for bacterial glycans and can respond rapidly to TI antigens administered systemically. However, many questions remain, including the factors restricting B cell entry, propagation, and selection in GALT, and the relationship between GALT sites along the GI tract.Gut-associated lymphoid tissues (GALT) are chronically activated by the intestinal microbiota, maintaining gut homeostasis and supporting immune responses. GALT differs from other lymphoid tissues in several ways, including its ability to propagate IgA responses against glycans and support the development of systemic B cells in certain species, such as humans. GALT is organized lymphoid tissue distributed along the gastrointestinal tract, with Peyer's patches being the most abundant in the terminal ileum. It lacks a capsule and afferent lymphatics, and its structure includes the follicle-associated epithelium (FAE), which contains antigen-sampling microfollicular (M) cells. GALT supports the maturation and propagation of B cells, including the development of marginal zone B (MZB) cells, which mediate rapid systemic immunity to T-cell-independent (TI) antigens. Recent advances in technologies, such as single-cell transcriptomics and imaging mass cytometry, have enhanced our understanding of GALT's unique features and its interactions with the microbiota. GALT's chronic activation by the microbiota leads to the formation of germinal centers (GCs), where B cells undergo affinity maturation and selection. In humans, GALT supports the development of innate-like MZB cells that circulate in the blood and reside in the spleen, contributing to protective immunity in the lungs. The presence of TI antigens from the gut microbiota and pre-existing GCs in GALT creates a unique environment where B cells can both mutate their V regions and be selected for higher affinities. GALT also plays a role in the maturation of MZB cells, which acquire specificity for bacterial glycans and can respond rapidly to TI antigens administered systemically. However, many questions remain, including the factors restricting B cell entry, propagation, and selection in GALT, and the relationship between GALT sites along the GI tract.