Making use of state-of-the-art virological, biochemical, cell biological (e.g. siRNA and haploid screens), and microscopy (e.g. life cell imaging and EM tomography) approaches, we study the role of picornavirus proteins and (hijacked) host factors in the formation and the architecture of the viral replication organelles as well as in the process of viral RNA synthesis that takes place in these specialised replication sites.