Two major leishmaniasis treatments have shown a significant decrease in effectiveness in the last few decades, mostly in the Indian subcontinent but also in other endemic areas. Drug resistance of Leishmania correlated only partially to treatment failure (TF) of pentavalent antimonials, and has so far proved not to be important for the increased miltefosine relapse rates observed in the Indian subcontinent. While other patient- or drug-related factors could also have played a role, recent studies identified several parasite features such as infectivity and host manipulation skills that might contribute to TF. This perspective aims to discuss how different parasitic features other than drug resistance can contribute to TF of leishmaniasis and how this may vary between different epidemiological contexts.