An enzyme that controls the maturation and long-term survival of immune cells called macrophages has been discovered, with implications for research on aging and inflammatory disease. Virtually all tissues are populated by tissue-resident macrophages – self-renewing, long-lived immune cells that maintain tissue health and homeostasis by clearing damaged cells and debris. In obese mice, for example, it suppresses inflammatory macrophage accumulation in adipose tissue and improves glucose tolerance. Then, transcriptional analyses of DHPS-deficient macrophages indicated a block in their ability to differentiate into mature tissue-resident macrophages, while proteomics revealed defects in cell adhesion and signaling pathways. Taken together, these findings pinpoint DHPS as a regulator of the pathway that drives the differentiation of monocyte-derived macrophages into tissue-resident macrophages.