Resilience to infections is equally defined by the host’s ability to clear the infecting pathogen and to resolve and mitigate secondary injury, and thus to restore and maintain tissue homeostasis. These physiological processes of resolution and repair, however, intersect with pathogenic responses in chronic organ fibrosis. The role of viral infections in fibrotic diseases are not well defined. We have recently identified a population of pulmonary macrophages that arises in patients with severe COVID-19 and fibroproliferative ARDS. These macrophages share core features with profibrotic macrophages in idiopathic pulmonary fibrosis or liver cirrhosis. Here we aim to dissect the signals that program profibrotic monocyte and macrophage responses in acute infections and chronic fibrosis in order to define checkpoints and potential therapeutic targets, with the aim of rewiring responses to tissue injury and restoring tissue homeostasis.