American trypanosomiasis is a widespread protozoal infection that affects the poorest and the most disadvantaged populations in the developing world. There is a lack of effective, affordable, and safe medicines for its treatment, mainly due to the low investment in R&D by the pharmaceutical industry. One alternative approach for the development of new drugs is the identification of bioactive natural compounds, which are particularly important for their structural diversity and their potential as novel pharmacophores. In this chapter, an overview of the investigations concerning the trypanocidal activity of plants, published over the period (2000–2010), will be presented. Either medicinal plants or isolated compounds will be considered. Data will be discussed under a critical point of view in relation with the challenge that implicates a drug discovery process from natural sources. The review will be focused on analyzing those published data dealing with the identification of new lead structures aimed at “bringing a drug to market.”