Epidemics of fatal visceral leishmaniasis caused by the intracellular protozoan Leishmania are a severe public health problem in tropical and subtropical regions of the world. One major drawback in the treatment of leishmaniasis is the emergence of resistance to current chemotherapeutics. Leishmanicidals have to be administered in low doses since commonly used drugs exhibit severe side effects, and hence drug resistance can appear rapidly. Since, to date, vaccination approaches have failed to enter clinical trials, chemotherapy based on small molecules is temporarily the exclusive treatment strategy. There is an urgent need for adding novel drugs with improved features to the pool of current chemotherapeutics. Many compounds derived from natural sources have pharmacological activities and may, thus, be of potential utility in drug development and biomedical research. Natural products, primarily plant-derived substances of diverse structural classes, have been described in the literature showing anti-leishmanial properties. In this review we provide a brief overview of the current treatment and the active principles of established drugs. Furthermore, we focus on the mechanisms of drug resistance and natural products that are promising leads for the development of novel chemotherapeutics.