Leishmaniasis is a disease caused by at least 17 different species of protozoan Leishmania parasites and currently affects around 12 million people living mostly in tropical and subtropical areas. Failure to treat leishmaniasis successfully is often due to drug resistance. However, there are no cellular and molecular markers of chemoresistance against leishmanicidal drugs and the only reliable method for monitoring resistance of individual isolates is the in vitro amastigote/macrophage model. It is thus necessary to find cellular and molecular markers that can be used systematically to identify the drug-resistant phenotype of the infecting parasites. Until now, whether drug resistance in Leishmania compromises parasite proficiency, e.g. in terms of infectivity or metabolism, has not been systematically evaluated. Therefore, here we examine whether the physiological changes expressed by drug-resistant Leishmania reflect a modification of parasite vitality in drug-resistant compared with drug-sensitive parasites. Finally, the clinical implications of drug resistance in Leishmania are also discussed.