The kinetoplastids are a group of protozoan parasites characterized by the presence of a unique organelle, called the kinetoplast, that is located inside a single mitochondrion and contains a large amount of DNA called kinetoplast DNA (kDNA). Kinetoplastids of medical and veterinary significance include Trypanosoma spp. (the etiological agents of human and animal African Trypanosomiasis, surra, dourine, and Chagas disease), and Leishmania spp. (the causative agents of the various forms of leishmaniasis). Millions of people, and their domesticated animals, living in endemic regions across the globe are at risk of these Neglected Tropical Diseases. All of the human and veterinary conditions can be disabling or fatal if not adequately treated, and no vaccines are available. However, drug treatment is hampered by the challenges of drug resistance and toxicity to the mostly very old drugs. We have been investigating propolis (a natural product made by bees from tree resins), and compounds isolated from it, as novel agents against Trypanosoma and Leishmania species. Our results show that propolis and some of the phytochemicals isolated from it, have no in vitro growth inhibition against mammalian cells, but displayed low EC₅₀ against Trypanosoma and Leishmania species, without a loss of activity against diamidine- and arsenical-resistant or phenanthridine-resistant T. brucei strains, or a miltefosine-resistant L. mexicana strain. These results provide sufficient scope for further investigations of propolis-derived natural compounds toward the rational development of sustainable drugs against these kinetoplastids.