Post-translational modifications play crucial parts in regulating protein function and thereby control several fundamental aspects of eukaryotic biology, including cell signalling, protein trafficking, epigenetic control of gene expression, cell-cell interactions, and cell proliferation and differentiation. In this Review, we discuss protein modifications that have been shown to have a key role in malaria parasite biology and pathogenesis. We focus on phosphorylation, acetylation, methylation and lipidation. We provide an overview of the biological significance of these modifications and discuss prospects and progress in antimalarial drug discovery based on the inhibition of the enzymes that mediate these modifications.