Chagas disease is a neglected tropical disease and a global public health issue. In terms of treatment, no progress has been made since the 1960s, when benznidazole and nifurtimox, two obsolete drugs still prescribed, were used to treat this disease. Hence, currently, there are no effective treatments available to tackle Chagas disease. Over the past 20 years, there has been an increasing interest in the disease. However, parasite genetic diversity, drug resistance, tropism, and complex life cycle, along with the limited understanding of the disease and inadequate methodologies and strategies, have resulted in the absence of new insights in drugs development and disappointing outcomes in clinical trials so far. In summary, new drugs are urgently needed. This Review considers the relevant aspects related to the lack of drugs for Chagas disease, resumes the advances in tools for drug discovery, and discusses the main features to be taken into account to develop new effective drugs.

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Chagas disease (CD) is a parasitic, systemic, chronic, and often fatal illness caused by infection with the protozoan Trypanosoma cruzi . The World Health Organization classifies CD as the most prevalent of poverty-promoting neglected tropical diseases, the most important parasitic one, and the third most infectious disease in Latin America. Currently, CD is a global public health issue that affects 6–8 million people. However, the current approved treatments are limited to two nitroheterocyclic drugs developed more than 50 years ago. Many efforts have been made in recent decades to find new therapies, but our limited understanding of the infection process, pathology development, and long-term nature of this disease has made it impossible to develop new drugs, effective treatment, or vaccines. This Review aims to provide a comprehensive update on our understanding of the current life cycle, new morphological forms, and genetic diversity of T. cruzi , as well as identify intervention points in the life cycle where new drugs and treatments could achieve a parasitic cure.