Little progress has been made since the 1960s and 1970s to widen the therapeutic arsenal against Trypanosoma cruzi, the causative pathogen of Chagas disease, which remains a frustrating and perplexing infectious disease. This chapter focuses on the strategic and operational challenges in the clinical drug development of a novel antitrypanosomal agent for Chagas disease. The various elements that contribute to a robust assessment of treatment effect including dose selection, choice of patient population, trial methodology, endpoint measures, and regulatory perspectives are discussed. The learnings herein should serve as resource to help researchers and other stakeholders optimize their clinical development plans and speed delivery of new medicines to patients with Chagas disease.