RNA replication is the central process during the infectious cycles of plus-stranded RNA viruses. Development of yeast as a model host and powerful in vitro assays with purified replicase complexes, together with reverse genetic approaches make tombusviruses, small plant RNA viruses, excellent systems to study fundamental aspects of viral RNA replication. Accordingly, in vitro approaches have led to the identification of protein-RNA interactions that are essential for template selection for replication and assembly of the functional viral replicase complexes. Moreover, genome-wide approaches and proteomics analyses have identified a new set of host proteins that affected tombusvirus replication. Overall, rapid progress in tombusvirus replication has revealed intriguing and complex nature of virus-host interactions, which make robust replication of tombusviruses possible. The knowledge obtained will likely stimulate development of new antiviral methods as well as other approaches that could make tombusviruses useful tools in biotechnological applications.