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Trypanosomatid parasites of the genus  Leishmania  are the causative agents of leishmaniasis, a neglected tropical disease with several clinical manifestations.  Leishmania major  is the causative agent of cutaneous leishmaniasis (CL), which is largely characterized by ulcerative lesions appearing on the skin. Current treatments of leishmaniasis include pentavalent antimonials and amphotericin B, however, the toxic side effects of these drugs and difficulty with distribution makes these options less than ideal. Miltefosine (MIL) is the first oral treatment available for leishmaniasis. Originally developed for cancer chemotherapy, the mechanism of action of MIL in  Leishmania  spp. is largely unknown. While treatment with MIL has proven effective, higher tolerance to the drug has been observed, and resistance is easily developed in an  in vitro  environment. Utilizing stepwise selection we generated MIL-resistant cultures of  L .  major  and characterized the fitness of MIL-resistant  L .  major . Resistant parasites proliferate at a comparable rate to the wild-type (WT) and exhibit similar apoptotic responses. As expected, MIL-resistant parasites demonstrate decreased susceptibility to MIL, which reduces after the drug is withdrawn from culture. Our data demonstrate metacyclogenesis is elevated in MIL-resistant  L .  major , albeit these parasites display attenuated  in vitro  and  in vivo  virulence and standard survival rates in the natural sandfly vector, indicating that development of experimental resistance to miltefosine does not lead to an increased competitive fitness in  L .  major .

Fitness and Phenotypic Characterization of Miltefosine-Resistant Leishmania major