ABSTRACT The endoplasmic reticulum (ER) of eukaryotic cells is an essential organelle with many critical functions including, protein secretion. Its function is closely tied to its morphology. Work in higher eukaryotes has shown that mutations in key proteins required to generate the ER tubular network cause specific growth and developmental defects. In contrast to higher eukaryotes, little is known of how the ER is shaped in early eukaryotes such as protozoa. ER structure in the protozoan parasite, Plasmodium is dynamic and stage-specific but its molecular determinants are unknown. To understand how the ER acquires its shape in different stages of Plasmodium, we identified homologs of key ER-shaping proteins including ones that contain a reticulon homology domain. One of these protein induces membrane curvature in vitro. P. berghei parasites lacking the protein have dysmorphic ER, an enlarged digestive vacuole, are severely attenuated in the asexual cycle but infect hepatocytes normally. We hypothesize that the putative Plasmodium ER-shaping proteins we identified have stage-specific roles in maintaining proper ER structure/function. This proposal will determine the contributions of these proteins in shaping the ER of erythrocytic and hepatic stages of Plasmodium, using morphological and ultrastructural studies of P. berghei gene-knockouts. It will determine the effect of their loss on a key ER function, protein trafficking in the parasite. Our study will provide the first causal link between ER architecture, protein trafficking and the ability of the malaria parasite to reside in different host environments.