A number of viruses and viral proteins interact with a dynamic sub-nuclear structure called the nucleolus. The nucleolus is present during interphase in mammalian cells and is the site of ribosome biogenesis, and has been implicated in controlling regulatory processes such as the cell cycle. Viruses interact with the nucleolus and its antigens; viral proteins co-localise with factors such as nucleolin, B23 and fibrillarin, and can cause their redistribution during infection. Viruses can use these components as part of their replication process, and also use the nucleolus as a site of replication itself. Many of these properties are not restricted to any particular type of virus or replication mechanism, and examples of these processes can be found in DNA, RNA and retroviruses. Evidence suggests that viruses may target the nucleolus and its components to favour viral transcription, translation and perhaps alter the cell cycle in order to promote virus replication. Autoimmunity to nucleolin and fibrillarin have been associated with a number of diseases, and by targeting the nucleolus and displacing nucleolar antigens, virus infection might play a role in the initiation of these conditions.