Updated FTP location. Life-cycle progression of the human malaria parasite Plasmodium falciparum in the human and mosquito hosts requires epigenetic mechanisms to regulate the stage-dependency of gene expression, including DNA and histone methylation. Methylation reactions require S-adenosylmethionine (SAM), a universal biological methyl donor whose synthesis is catalyzed by the enzyme S-adenosylmethionine synthetase (SAMS). In P. falciparum, PfSAMS is encoded by a single gene and has been suggested to be crucial for malaria pathogenesis and transmission; however, to date PfSAMS has not been fully characterized. To gain deeper insight into the function of PfSAMS, we generated a conditional gene knockdown (KD) using the pSLI-glmS system. We show that PfSAMS is expressed in the cytosol and nucleus of blood stage parasites. PfSAMS-KD results in reduced histone methylation marks and leads to impaired intraerythrocytic growth and gametocyte development. To further determine the interaction network of PfSAMS we performed BioID analyses. We identified 664 nuclear and 213 cytosolic interactors linked to biological processes like transcriptional and cell cycle regulation. Our interaction data further unveil PfSAMS-specific interaction clusters of proteins involved in DNA replication, transcription and translation as well as proteostasis. Our findings emphasize the key roles of PfSAMS during intraerythrocytic growth and sexual stage development.