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Novel technologies that include recombinant pathogens and rapid detection methods are contributing to the development of drugs for neglected diseases. Recently, the results from the first high throughput screening (HTS) to test compounds for activity against Trypanosoma cruzi trypomastigote infection of host cells were reported. We have selected 23 compounds from the hits of this HTS, which were reported to have high anti-trypanosomal activity and low toxicity to host cells. These compounds were highly purified and their structures confirmed by HPLC/mass spectrometry. The compounds were tested in vitro, where about half of them confirmed the anti-T. cruzi activity reported in the HTS, with IC50 values lower than 5 µM. We have also adapted a rapid assay to test anti-T. cruzi compounds in vivo using mice infected with transgenic T. cruzi expressing luciferase as a model for acute infection. The compounds that were active in vitro were also tested in vivo using this assay, where we found two related compounds with a similar structure and low in vitro IC50 values (0.11 and 0.07 µM) that reduce T. cruzi infection in the mouse model more than 90% after five days of treatment. Our findings evidence the benefits of novel technologies, such as HTS, for the drug discovery pathway of neglected diseases, but also caution about the need to confirm the results in vitro. We also show how rapid methods of in vivo screening based in luciferase-expressing parasites can be very useful to prioritize compounds early in the chain of development., Author Summary Chagas is a devastating disease affecting about 100 million people in Latin America. The drugs available for treatment against the causative agent, the parasite Trypanosoma cruzi, have associated toxicity and are not completely effective against the chronic form of the disease, which is the most common presentation in the clinic. There is a great need for new drugs against this disease. Novel technologies in drug development are now being applied for the search of new compounds against Chagas. Taking advantage of a high throughput screening performed recently to identify compounds active against T. cruzi replication in host cells in vitro, we have selected 23 compounds, which have been re-tested to selected active ones. We have also adapted a transgenic T. cruzi expressing luciferase, which allows for direct visualization when mice are infected. These parasites have been used to establish a model for acute Chagas disease useful for drug testing in mice. Using this method, we have tested the activity of the selected compounds and found two compounds with strong anti-T. cruzi activity in mice.