Leishmaniasis, African sleeping sickness and Chagas disease, caused by the kinetoplastid parasites Leishmania spp, Trypanosoma brucei and Trypanosoma cruzi, respectively, are among the most important parasitic diseases, affecting millions of people and considered to be within the most relevant group of neglected tropical diseases. The main alternative to control such parasitosis is chemotherapy. Nevertheless, the current chemotherapeutic treatments are far from being satisfactory. This review outlines the current understanding of different drugs against leishmaniasis, African sleeping sickness and Chagas disease, their mechanism of action and resistance. Recent approaches in the area of anti-leishmanial and trypanocidal therapies are also enumerated, new modulators from the mode of action, development of new formulations of old drugs, therapeutic switching and “in silico” drug design.