Leishmaniasis, a disease caused by protozoa of the <i>Leishmania</i> species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of <i>Leishmania</i> parasites with good selectivity relative to the host macrophages. Early lead <b>34</b> was rapidly acting and possessed good potency against <i>L. mexicana</i> (EC<sub>50</sub> = 120 nM), 30-fold selectivity for the parasite relative to the macrophage (EC<sub>50</sub> = 3.7 μM), and also blocked proliferation of <i>Leishmania donovani</i> parasites resistant to antimonial drugs. Finally, another early lead, <b>27</b>, which exhibited reasonable in vivo tolerability, impaired disease progression during the dosing period in a murine model of cutaneous leishmaniasis. These results suggest that the arylquinolines provide a fruitful departure point for the development of new antileishmanial drugs.