Misassembled proteins can be degraded by a process called endoplasmic reticulum-associated degradation (ERAD). Using a bioinformatics approach, this study showed that protozoan pathogens contain a simpler ERAD network than higher eukaryotic cells. Because of this, Plasmodium falciparum was very sensitive to the inhibition of ERAD components, in particular signal peptide peptidase (SPP) inhibitors, which disrupted the degradation of unstable proteins and inhibited proteolytic activity. SPP inhibitors were also active against liver-stage malaria parasites and several other pathogenic protozoan parasites, suggesting that SPP could be a potential pan-protozoan drug target.