The control of diseases caused by trypanosomatids, such as those caused by Leishmania spp. and Trypanosoma cruzi, is focused on the use of drugs to treat infected patients, which are limited by their high cost, high toxicity and safety concerns, in the absence of an effective and safe vaccine for use in humans. Therefore, new strategies for vaccines have emerged in the last years and better perspectives for the future are expected. In this context, the aim of this chapter is to discuss the past, present and future of vaccines against Leishmania spp. and Trypanosoma cruzi. In addition, we indicate important aspects for the development of anti-trypanosomatids vaccines.