Purpose of Review: Despite recent advances, Chagas disease is still a public health issue that requires more efforts in order to develop efficient and safe drugs. Plants and fungi are the main source for semi-synthetic natural-inspired new molecules to treat human illness. In the present work, we summarize the main findings of natural-derived and semi-synthetic alkaloids against Trypanosoma cruzi. Recent Findings: Over the last 10 years, at least seven alkaloids groups with structural modifications, including 130 molecules and almost 100 semi-synthetic compounds derived from natural alkaloids, including hybrids molecules, modifications of aliphatic chain extension, chemical groups, and heteroatoms, were analyzed for its toxicity over parasites and mammalian cells. Summary: According to the available data, there are a good number of promising natural and/or semi-synthetic alkaloids that would meet the criteria to become candidates in the drug discovery process against Trypanosoma cruzi parasites. Main scaffolds that deserve special attention are natural quinolones, isoquinolines, and semi-synthetic hybrids molecules. © 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.