Cutaneous leishmaniasis remains ignored in therapeutic drug discovery programs worldwide. This is mainly because cutaneous leishmaniasis is frequently a disease of impoverished populations in countries where funds are limited for research and patient care. However, the health burden of individuals in endemic areas mandates readily available, effective, and safe treatments. Of the existing cutaneous leishmaniasis therapeutics, many are growth inhibitory to Leishmaniaparasites, potentially creating dormant parasite reservoirs that can be activated when host immunity is compromised, enabling the reemergence of cutaneous leishmaniasis lesions or worse spread of Leishmaniaparasites to other body sites. To accelerate the identification and development of novel cutaneous leishmaniasis therapeutics, we designed an integrated in vitroand in vivoscreening platform that incorporated multiple Leishmanialife cycles and species and probed a focused library of pharmaceutically active compounds. The objective of this phenotypic drug discovery platform was the identification and prioritization of bona fidecytotoxic chemotypes toward Leishmaniaparasites. We identified the Food and Drug Administration-approved drug auranofin, a known inhibitor of Leishmaniapromastigote growth, as a potent cytotoxic anti-leishmanial agent and inducer of apoptotic-like death in promastigotes. Significantly, the anti-leishmanial activity of auranofin transferred to cell-based amastigote assays as well as in vivomurine models. With appropriate future investigation, these data may provide the foundation for potential exploitation of gold(I)-based complexes as chemical tools or the basis of therapeutics for leishmaniasis. Thus, auranofin may represent a prototype drug that can be used to identify signaling pathways within the parasite and host cell critical for parasite growth and survival.