Leishmania drug resistance and particularly antimony resistance still continues to emerge in different part of the world. Because visceral and cutaneous leishmaniasis are transmitted in foci with zoonotic or anthroponotic life-cycles, the link between chemotherapeutic resistance and the selection for drug resistance, through drug consumption, cannot be as obvious for all forms of leishmaniasis. The underlying factors that trigger the selection of antimony resistant parasites are poorly studied in regard to environmental aspects. Recently, a correlation between the emergence of antimony unresponsiveness in India and water arsenic contamination has been raised. The presence of some yet unidentified environmental factors driving the selection of antimony resistant Leishmania populations in a zoonotic context of leishmaniasis is also currently questioned. The identification of key molecules involved in the selection of antimony resistance and their importance in the selective process have to be re-evaluated in light of the environment were all the hosts of Leishmania (mammalian and arthropod) evolved. These new insights will help to (i) address the risk of therapeutic failure associated with the emergence of drug-resistance and (ii) propose new therapeutic protocols to aim at reducing the risk of resistance in endemic areas.