In 2004, visceral leishmaniasis (kala-azar) maintains its status as a neglected, if not "most neglected" disease. Lack of affordable new drugs, still a basic unsolved problem, has also been joined by additional therapeutic obstacles including large-scale resistance to pentavalent antimony (Sb) in India and coinfection with human immuno-deficiency virus in all endemic regions. Nevertheless, available treatment options have actually expanded because the energetic clinical trials effort of the past decade has yielded tangible advances. This progress includes successful application of less expensive generic Sb; rediscovery of the high-level efficacy of amphotericin B; implementation of short-course parenteral regimens (lipid formulations of amphotericin B); potential to replace Sb and amphotericin B with price-capped paromyomycin; and identification of the first effective oral agent (miltefosine). How to sustain and move this progress ahead, make new advances practical (e.g., affordable, and therefore, deployable), and how to translate promising experimental approaches into actual therapy remain difficult next steps in the treatment of kala-azar.