Functional genome-wide screens in Plasmodium spp. parasites, the causative agents of malaria, have been lacking, as they are refractory to genetic manipulation. Now, a new study by Bushell et al. reports the findings of an in vivo genetic screen that identified essential genes and pathways that are required for parasite growth. The authors created pools of knockout Plasmodium berghei mutants covering 2,578 genes (representing >50% of the parasite genome), and infected mice with these pools of mutants. They used next-generation sequencing to measure the relative growth rate of the genetically modified parasites and observed that approximately 63% of P. berghei genes were required for normal asexual blood stage growth in vivo. By contrast, they found that many genes at the host–pathogen interface, such as genes that are involved in erythrocyte invasion and immune evasion, were redundant, which suggests that opposing evolutionary pressures have shaped the Plasmodium spp. genome.