Resistance to first‐line anti‐malarial drugs has accelerated the need for new drugs with novel targets for effective malaria treatment. Many of the current anti‐malarial drugs work in part by overwhelming the parasite stress response. In eukaryotes, the oxidative stress response machinery includes antioxidants as well as SUMOylation, a post‐translational modification that involves the covalent attachment of small ubiquitin‐related modifiers (SUMOs) to proteins. We hypothesize that SUMOylation plays an essential role in parasite cell stress survival, and that parasite‐specific SUMOylation inhibitors could prove effective in combination with current anti‐malarial drugs. We have previously demonstrated that human and Plasmodium falciparum (Pf) SUMO conjugation systems have biochemically distinct E1‐E2 enzyme interactions, suggesting a target for drug development. Here, we use x‐ray crystallographic studies to further define and compare the human and Pf E1‐E2 interaction. We have identified non‐conserved and structurally distinct surface residues that will help guide the identification of parasite‐specific inhibitors of SUMOylation.This research was funded in part by the National Institutes of Health (GM060980), the Johns Hopkins School of Public Health Sommer Scholar's Program, and the Johns Hopkins Malaria Research Institute.