Malaria is a devastating infectious disease elicited by protozoan parasites of the genus Plasmodium. In 2012, malaria caused over 200 million clinical cases and close to 700’000 deaths, mostly among young children in sub-Saharan Africa. Human-to-human transmission of malaria parasites via Anopheles mosquitoes represents the biggest obstacle for efficient malaria control. Infection of the insect vector requires the obligate ingestion of mature sexual precursor forms called gametocytes via the blood meal. Gametocytes are constantly produced during human blood infection where asexually replicating parasites undergo unlimited vegetative growth. During each round of proliferation a small subset of parasites undergo an irreversible switch from vegetative growth to cell cycle exit and sexual differentiation. This provides a continuous source of mature gametocytes, which are the only forms capable of infecting the mosquito vector and are therefore essential for malaria transmission. The regulatory basis of this cell fate decision process has long remained one of the largest mysteries in the biology of malaria parasites. Recent seminal work now uncovered AP2-G, a key transcription factor essential for gametocyte commitment. The switch from asexual proliferation to gametocyte differentiation is controlled through an epigenetic mechanism that regulates the expression of AP2-G. In asexual parasites, the ap2-g locus is silenced by heterochromatin protein 1 (HP1), an evolutionary conserved regulator of heritable gene silencing. Conditional depletion of HP1 is sufficient to activate AP2-G expression and to cause an irreversible switch to sexual differentiation. The main goal of this research proposal is to elucidate the molecular basis of the sexual conversion switch in P. falciparum, which causes the most virulent form of malaria in humans. I will realise this by pursuing three major objectives designed to identify the mechanisms responsible for heritable silencing and activation of the cell fate decision factor PfAP2-G and to investigate the role of PfAP2-G in early differentiation of malaria transmission stages. I propose a multi-faceted approach combining innovative reverse genetics methods with high throughput sequencing and proteomics technology and automated fluorescence imaging. This will identify regulatory factors and processes involved in the mechanism establishing silenced chromatin at the pfap2-g locus and in the upstream molecular pathway triggering activation of PfAP2-G expression. Furthermore, I will elucidate the direct consequences of PfAP2-G activation on the transcriptional and chromatin landscape in early gametocytes. The anticipated results will deliver unprecedented insight into this crucial and unique cell fate decision processes and will uncover new possibilities for the discovery and development of transmission-blocking drugs. Importantly, since pfap2-g is conserved in all Plasmodium species the acquired knowledge will most likely also be valid for other species infecting humans including P. vivax.