Infection by protozoan parasites remains a major cause of global human morbidity and economic hardship. With annual death rates exceeding a million people and even higher numbers afflicted by disability and compromised agricultural productivity, the organisms causing tropical diseases like leishmaniasis, trypanosomiasis, malaria, and toxoplasmosis represent an ongoing challenge. Whilst new compounds to treat malaria and toxoplasmosis have been discovered and deployed recently, this progress has not been mirrored for trypanosomiasis or leishmaniasis. Climate change, increased mobility, and mass migration also undermine our ability to control diseases caused by these organisms, and the need for new drugs to combat resistance and new strains of parasites remains acute. Nonetheless, considerable advances in understanding the cell biology of all of these infectious agents have been made, and this new knowledge is poised to contribute strongly to control strategies. In this short article, we will focus on the nuclear biology of trypanosomatid and Apicomplexan parasites, highlighting aspects that appear to represent potentially key adaptations that facilitate infection and, thus, the disease burden of these old enemies.