Experimental research into malaria biology and pathogenesis has historically focused on two model systems, in vitro culture of the human parasite Plasmodium falciparum and in vivo infections of laboratory animals using rodent parasites. While there is clear value in having a manipulatable animal model for studying malaria, there have occasionally been controversies around how representative the rodent model is of the human disease, and therefore significant emphasis has been placed on the similarities between the two biological systems. By focusing on basic nuclear functions, we wish to highlight that identifying key differences in the parasites and their interactions with their mammalian hosts can be equally informative and provide remarkable insights into the biology and evolution of these important infectious organisms.