• Adventitial perivascular niches contain specialized stromal and immune cells.

• Tissue-resident type 2 and regulatory lymphocytes are enriched in the adventitia.

• Adventitia contain lymphatics, neurons, and fibroblast-like stromal cells.

• Adventitial stromal cells are critical tissue immunomodulators.

• Adventitial-immune crosstalk impacts tissue physiology and inflammatory response.

Advances in microscopy, genetically modified mice, and single-cell RNA sequencing have begun to deconvolute the composition and function of tissue immune niches. Here we discuss the evidence that the adventitia, the outermost layer of larger blood vessels, is a conserved niche and tissue immune outpost for multiple immune cells, including group 2 innate lymphoid cells (ILC2) and subsets of tissue-resident memory T cells, macrophages, and dendritic cells. We also describe the unique non-immune composition at adventitial regions, including fibroblast-like stromal cell subsets, lymphatic and blood endothelial cells, and neurons, and review how immune-stromal crosstalk impacts regional tissue immunity, organ adaptation, and disease.