Plus-stranded RNA viruses recruit cellular membranes and subvert cellular proteins involved in lipid biosynthesis to build viral replicase complexes (VRCs) and replication organelles. We use tombusviruses (TBSV), which are small (+)RNA viruses, as model plant viruses to study virus replication, recombination, and virus - host interactions using yeast (Saccharomyces cerevisiae) as a surrogate host. 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 a dozen co-opted host proteins, sterols and phosphatidylethanolamine in tombusvirus VRC assembly and viral RNA synthesis. We also present data that Tombusviruses induces the formation of membrane contact sites, where membranes are juxtaposed, to channel lipids to the replication sites. Using in vitro viral replication assay with artificial vesicles, we show stimulation of tombusvirus replication by PE and sterols. Finally, we show evidence that TBSV usurps the ESCRT machinery to form vesicle-like structures to build VRCs in a protected microenvironment involving peroxisomes, early endosomes and ER.