Neglected tropical diseases (NTDs) affect more than one billion people (one-sixth of the world's population) and cause almost 550,000 deaths annually, with a nearly dry drug discovery pipeline due to low investment returns and a wide translational gap in academic research—though public-private partnerships have started to close this gap over the past decade. Among NTDs, diseases caused by Trypanosoma (responsible for Chagas disease in South America and sleeping sickness in Africa) and Leishmania (causing cutaneous and visceral infections endemic in 88 countries) are grouped under the "most neglected diseases" due to their concentration in poorest rural areas, low visibility in Western societies, and status as the three NTDs with the highest death rates. Vaccine development is unlikely due to extreme antigenic variation and lack of resources for translational work and large trials, so chemotherapy remains the only treatment option, but most modalities rely on over 50-year-old drugs (except recent encouraging results with miltefosine and paramomycin) that suffer from poor efficacy, high toxicity, and increasing resistance. Important advances in anti-trypanosomatid drug discovery have accelerated over the past decade with improved in vitro cultivation methods, enhanced genetic accessibility, completed genome sequences for key trypanosomatid species, and increased prominence on agendas of well-resourced public figures and foundations; however, trypanosomiases and leishmaniases remain incurable and fatal, an urgent issue for the academic pharmaceutical community. The objective of this Perspective is to report on possible innovative drug discovery approaches to the development of drug candidates for NTDs, propose the multitarget drug design strategy as a means to overcome the highlighted challenges, illustrate examples of how this strategy has been explored to design innovative lead candidates against trypanosomiases and leishmaniases, and first present a brief overview of the most validated and novel parasitic targets for developing new chemical entities against these NTDs.