Chagas disease is the major endemic disease in South and Central America caused by a trypanosomatid parasite (Trypanosoma cruzi). The current treatment relies on two old and nonspecific chemotherapeutic agents, Nifurtimox and Benznidazole. Despite the major advances that have been made in the identification of specific targets that afford selectivity, the drugs used today have serious side effects. Furthermore, differences in drug susceptibility among different T. cruzi isolates have led to varied parasitological cure rates depending on the geographical region. There is, therefore, an urgent need for the development of new antichagasic drugs. In this regard we have spent more than a decade in the search for more effective agents able to compromise the proliferation of T. cruzi. We began our research with our own compounds and then continued with compounds from other researcher groups. We systematically characterized representatives of a wide range of different chemical families. In this review we summarize our ongoing efforts to identify potential anti-T. cruzi agents using our compound-library. It is discussed and presented the structure- activity relationship observed among the different groups of chemical families.