Tissue-resident macrophages (TMs), including epidermal Langerhans cells (LCs), are long-lived cells able to proliferate. Their ontogeny and adaptation to different organs have been studied in great details, yet their physiological maintenance deserves further investigations. Autophagy, a catabolic process regulated by autophagy-related (Atg) genes, prevents accumulation of harmful cytoplasmic components and mobilizes energetic reserves in long-lived and self-renewing cells. Recently, we found that Atg5-deficient LCs undergo apoptosis as a result of lipid metabolism dysregulation. Here, we propose that autophagy allows TMs to manage lipid stocks and ensure long-term maintenance. We will first validate this in murine and human LCs, then verify whether it holds true for TMs of the lung, liver and lymph nodes. Finally, we will test whether autophagy could permit TMs to adapt to cellular stress and limit inflammation induced by metabolic alterations, irradiation, aging and viral infection. Altogether, our results will introduce a new paradigm on the maintenance of TMs in a broad range of organs under physiological and inflammatory conditions.