Macrophages are immune cells that are present in essentially every organ of the body. Besides classical functions in immunity, they are also important for normal functioning of the surrounding tissue and its regeneration. Recent evidence shows that resident macrophages can originate from embryonic progenitors and be maintained in tissues long term by local proliferation. This self-renewal ability, however, appears to decline with age, with potentially major consequences for the response to infection, the resolution of inflammation and the ability for tissue regeneration. Understanding the decline of self-renewal in the aging macrophage may thus hold key elements for maintaining healthy tissue integrity. Drawing from analogies to stem cell self-renewal we want to decipher the molecular and cellular parameters of macrophage self-renewal and its decline with age.