A pathogen's fitness relates to all biological processes that ensure its survival, reproduction, and transmission in specific conditions. These often include the presence of drugs, forcing pathogens to adapt and develop drug resistance in order to survive. The acquisition of a drug-resistant trait usually comes at a cost, making drug-resistant parasites less fit than their wild-type counterparts. This has important implications on the development of drug resistance and on the frequency of treatment failure cases in endemic regions. Treatment failure in patients suffering from leishmaniasis has been observed for most antileishmanials, but could not always be correlated to drug resistance of the infecting parasite. One similitude of both pentavalent antimonial and miltefosine treatment failure, however, relates to changes in parasite fitness. In the specific case of Leishmania donovani, for example, this may contrast with the usual fitness cost observed in natural drug-resistant organisms and highlights parasite fitness as an important contributor to treatment failure in visceral leishmaniasis in the Indian subcontinent. In this final chapter, we will canvass the knowns and the unknowns of Leishmania fitness at different parasite life stages and for different Leishmania species and discuss its relevance for the development and spread of drug resistance and/or treatment failure in the field. We will also propose new research avenues for leishmaniasis drug development and control in the context of current elimination efforts.