In search of novel therapeutic targets, we performed comprehensive <i>in vitro</i> and <i>ex vivo</i> mapping of the signaling pathways upstream and downstream of antioxidant transcription factor [nuclear factor erythroid 2-related factor 2 (Nrf2)] in cutaneous leishmaniasis (CL), by combining functional assays in human and murine macrophages with a systems biology analysis of <i>in situ</i> (skin biopsies) CL patient samples.