Macrophages are immune cells that can be found in all organs. We had demonstrated that macrophages develop before birth from newly identified embryonic precursors that seed the tissues before birth, acquire a unique tissue-specific functional specialization in each organ and then self-maintain throughout life without any contribution from circulating adult precursors such as monocytes. However, we have very recently found that when adult monocytes get access to the empty macrophage niche in the liver or the lung they acquire identical tissue-specific macrophage functions and self-maintenance capacities as macrophages of embryonic origin. This paves the way towards monocyte-based cellular therapy in diseases associated with macrophage dysfunction. This includes a disease known as pulmonary alveolar proteinosis that develops in patients in which macrophages fail to clear surfactant proteins in the lungs. Using a mouse model, we have demonstrated that a single transfer of monocytes can cure this rare disease. This ERC grant aims at identifying the tissue-derived factors that imprint a unique functional specialization in each organ and provide the self-maintenance capacity to macrophages. This knowledge should permit the development of novel therapies for diseases in which macrophages play a central role.