In adult Drosophila, the role and regulation of blood cells has been controversial and active hematopoietic sites have been proposed. Here we demonstrate that the main activity of the blood cell system in adult Drosophila lies in immunity. We show that the vast majority of blood cells, or hemocytes, are actively phagocytosing macrophages (plasmatocytes). As in many insects, hemocytes in Drosophila accumulate in clusters at the ostia of the adult heart. However, we find that the largest reservoir of adult hemocytes is the extensive respiratory epithelium of the thorax and head (tracheal air sacs), equivalent to the vertebrate lungs. Colonization of these areas depends on (1) developmental timing, in particular the completion of residual phagocytosis of larval tissue in the young adult, and (2) infection-induced localization following exposure to gram-negative or gram-positive bacteria. Hemocyte residence correlates with sites of particle accumulation after injection, illustrating connections of the respiratory tissues with the hemolymph through the open circulatory system. Using time- and tissue-specific permanent genetic lineage tracing, we show that more than half of the adult macrophages derive from the embryonic lineage of Drosophila hemocytes. Genetic and cell biological approaches for the detection of hemocyte proliferation, and the continuous decline of total hemocyte numbers over the course of adult life, do not provide any signs of active blood cell homeostasis or proliferation, both under unchallenged or immune challenged conditions. Consistently, the GATA factor Serpent (srp) marks actively phagocytosing macrophages in the adult animal, in contrast to its expression in prohemocytes during embryonic and larval development. To determine the role of hemocytes in the adult fly, we examined the immune response to bacterial challenge in genetically hemocyte-ablated animals. Interestingly, we find that hemocytes have a key role as sentinels of bacterial infection, promoting the induction of an antimicrobial peptide specifically in the respiratory tissue. We propose the respiratory epithelium of the tracheal air sacs as important immune tissue, which is directly linked with cellular immunity and the blood cell system in adult Drosophila.