After a mosquito bite, the sporozoite forms of Plasmodium spp. — the causative agents of malaria — enter the bloodstream and are transported to the liver where they replicate inside hepatocytes. Blood-stage Plasmodium infection has been shown to induce innate immune responses, but whether the liver stage of malaria infection activates the innate immune system is less clear. Using RNA sequencing techniques, Kappe and colleagues analysed gene expression data from mouse livers after infection with attenuated Plasmodium yoelii, which only develop into liver-stage forms. They found that the parasites induced an innate immune response in the liver that was mediated by type I interferons (IFNs) and IFNγ, and mice that lacked IFNγ, the type I IFN receptor or IFN-regulatory factor 3 could not suppress liver-stage infection. Thus, in mice, innate immune responses are induced during malaria liver-stage infection, and this response can limit parasite development prior to the infection of red blood cells.