The current commitment of the pharma industry, nongovernmental organizations and academia to find better treatments against neglected tropical diseases should end decades of challenge caused by these global scourges. The initial result of these efforts has been the introduction of enhanced combinations of drugs, currently in clinical use, or formulations thereof. Phenotypic screening based on intracellular parasite infections has been revealed as the first key tool of antileishmanial drug discovery, because most first-in-class drugs entering Phase I trials were discovered this way. The professional commitment among stakeholders has enabled the availability of a plethora of new chemical entities that fit the target product profile for these diseases. However, the rate of hit discovery in leishmaniasis is far behind that for other neglected diseases. This review defends the need to develop new screening methods that consider the part played not only by intracellular parasites but also by the host’s immune system to generate disease-relevant assays and improve clinical outcomes.