Expression of viral genes results in the modulation of cellular metabolism to support virus replication. Poliovirus infection of HeLa cells induces a dramatic rearrangement of intracellular membrane structures: virtually all cellular organelles except mitochondria are converted into virus replication vesicles. Although this phenomenon is known for almost half a century, very few mechanistic details explaining this transformation are understood. Recently we found that small GTPases, Arf, key components of the secretory pathway, translocate to sites of poliovirus RNA replication in infected cells, and that two poliovirus proteins, 3A and 3CD, can independently induce such translocation in vitro. Our most recent work shows the recruitment to viral replication complexes of activators of Arf, specific guanine nucleotide exchange factors (GEFs). Diversion of these GEFs from their normal activities in the secretory pathway provides a plausible explanation for the inhibition of protein secretion in poliovirus-infected cells as well as for the sensitivity of poliovirus infection to brefeldin A, a drug known to inhibit the secretory pathway. Identification of these cellular components defines a new class of host factors involved in virus replication complex formation and allows us to propose a hypothesis for remodeling of endoplasmic reticulum membranes into poliovirus replication complexes.