Cell entry and egress are essential steps in the viral life cycle that govern pathogenesis and spread. Mammalian orthoreoviruses (reoviruses) are nonenveloped viruses implicated in human disease that serve as tractable models for studies of pathogen-host interactions. In this review we discuss the function of intracellular vesicular transport systems in reovirus entry, trafficking, and egress and comment on shared themes for diverse viruses. Designing strategic therapeutic interventions that impede these steps in viral replication requires a detailed understanding of mechanisms by which viruses coopt vesicular trafficking. We illuminate such targets, which may foster development of antiviral agents.