Leishmaniasis, a parasitic disease resulting from infection of macrophages by obligate intracellular parasites of genus Leishmania, is prevalent in tropical and subtropical regions of 88 countries, affecting about 12 million people in the world. Leishmaniasis displays a spectrum of clinical manifestations, ranging from mucocutaneous and cutaneous lesions to visceral leishmaniasis, which is usually fatal for untreated patients. Moreover, significant increases in the rate of Leishmania-HIV coinfections across the world and cases of resistant parasites are aggravating this problem. Chemotherapy is the only effective treatment for leishmaniasis. However, the growing incidence of resistance for most of the antileishmanial drugs in endemic and nonendemic regions has seriously hampered their use in these regions. The present chapter briefly illustrates leishmaniasis epidemiology, occurrence, parasite biology, drug targets, bioavailability and metabolism, and treatment around the world and also critically discusses the key points in alkaloids-based drug discovery protocols.