Malaria parasites of the Plasmodium spp. have complex life cycles that include multiple stages in a vertebrate host and a mosquito vector, requiring strong regulation of their transcriptional programs for life cycle progression and survival. Epigenetic mechanisms controlling gene expression have been shown to be important for parasite proliferation during the intra-erythrocytic developmental cycle, and evidence is emerging for a role of such mechanisms in other life cycle stages. In particular, parasite-specific genes involved in pathogenesis, evasion of host immune responses, invasion of host cells, and life cycle progression are regulated at the epigenetic level. In this chapter, the various processes involved in the regulation of these parasite-specific genes and gene families will be discussed. In addition, the changes observed at the level of local chromatin structure and global nuclear organization will be described. Finally, the promise of epigenetic regulators as targets of novel antimalarial drugs will be addressed. Collectively, these topics provide insight into the unique biology of Plasmodium spp. and highlight the areas where additional research is necessary for an increased understanding of gene regulation in this deadly parasite.