Plasmodium falciparum has 60 var genes encoding distinct antigenic forms of the virulence protein PfEMP1 (P. falciparum erythrocyte membrane protein 1). The parasite expresses only one var gene at any time point during infection to avoid detection by the immune system, but the mechanism controlling the silencing of the other 59 var genes was unknown. Now, Jiang et al. show that var gene silencing is regulated by the histone lysine methyltransferase PfSETvs (previously known as PfSET2). Knockout of PfSETvs led to a strong reduction in trimethylation of histone H3 lysine 36 along the entire body of var genes and to transcription of almost all var gene family members. Notably, confocal microscopy showed that knockout of PfSETvs resulted in the expression of multiple PfEMP1 variants at the surface of infected red blood cells.