Down‐regulation of both the malarial eIF‐5A and dhs genes by in vitro and in vivo silencing led to decreased transcript levels and protein expression and, in turn, to low parasitemia, confirming a critical role of hypusination in eIF‐5A for proliferation in Plasmodium. To further investigate whether eIF‐5A and the activating enzyme DHS are essential for Plasmodium erythrocytic stages, targeted gene disruption was performed in the rodent malaria parasite Plasmodium berghei. Here, DHPS is linked to parasitic infectious disease.