Virus – host interactions are currently among the most intensively studied research areas due to the promising new antiviral approaches emerging from these studies. Indeed, RNA viruses, which are important and emerging human, animal and plant pathogens, exploit host cells by recruiting host factors and escaping host antiviral responses. RNA viruses induce the deformation of cellular membrane structures to build extensive viral replication organelles. Approaches interfering with virus replication could be key to limit the significant harm caused by viruses to human health and major losses in agriculture. We study tombusviruses, which are small RNA viruses, as model plant viruses to study virus replication and virus - host interactions using yeast (Saccharomyces cerevisiae) as a surrogate host. Since viruses are intracellular parasites that use the ample resources of eukaryotic cells, it is feasible to study virus replication in model eukaryotic yeast cells. Several systematic genome-wide screens and global proteomic and lipidomic approaches have led to the identification of ~500 host proteins/genes that are implicated in TBSV replication. We characterized the role of 30 co-opted host proteins, sterols and phospholipids in tombusvirus replication. Finally, we also show evidence that tombusviruses usurp the glycolytic (metabolic) pathway to obtain energy to build the extensive virus replication organelles. Altogether, this virus-host system allows for rapid discovery of novel cellular factors affecting plant virus replication. This advance could immensely help other scientists working with less tractable, but devastating viral pathogens for which similar studies are currently more difficult to conduct.