Reduced efficacy, difficulties of administration and increasing frequency and severity of adverse events of pentavalent antimony have stimulated the quest for new anti-leishmanial drugs. Several clinical studies in Latin America testing injectable, oral and topical anti-leishmanial drugs have yielded inconsistent results. Since 1998 Indian researchers have conducted clinical trials evaluating hexadecylphosphocoline (miltefosine) in patients with visceral leishmaniasis and in 1999 clinical studies were initiated in Colombia in patients with cutaneous leishmaniasis. Up to date, more than 2,500 patients have been treated with miltefosine in India (visceral by L. donovani) and Colombia (cutaneous caused by L. panamensis) obtaining cure rates over 91% when a dose of 2.5 mg/kg/day during 28 days was used, with no difference between naïve and relapsing patients. In Guatemala the overall cure rate for patients with cutaneous leishmaniasis was 53% (33% for L. braziliensis; 60% for L. mexicana) while in Afghanistan the cure rate of patients with L. tropica was 63%. Patients with diffuse cutaneous leishmaniasis, mucosal disease and co-infected with HIV have been treated with initial success; however these diseases have frequent relapses. Mild gastrointestinal events (i.e. nausea, vomiting and diarrhoea) were present in 35 to 60% of patients included in clinical trials and 10 to 20% had a mild increase in transaminases and creatinine levels. Miltefosine, originally an antineoplastic drug, has a potent leishmanicidal activity as consequence of its interference in parasite metabolic pathways and the induction of apoptosis, has demonstrated efficacy against L. donovani visceral disease and L. panamensis cutaneous disease. Now, miltefosine must demonstrate its efficacy against other species associated with diverse clinical presentations.