Leishmaniasis, caused by the trypanosomatid protozoan Leishmania, is endemic in 98 countries worldwide, with morbidity and mortality increasing daily. Despite available drugs, leishmaniasis faces the challenge of emerging resistance and toxicity concerns for current drug regimes. Identification of anti-leishmanial compounds representing new chemistry and novel mechanisms of action is essential to populate the drug discovery pipeline. The in vitro assays currently available have shown poor translational outcomes, with high compound attrition rates. It is therefore imperative that more physiologically relevant assays are developed to identify anti-leishmanial compounds. This review provides an overview of the disease, current treatment options and compares the various technologies and assay formats currently available for leishmanial drug discovery.