Most viral infections are self-limiting, resulting in either clearance of the pathogen or death of the host. However, a subset of viruses can establish permanent infection and persist indefinitely within the host. Even though persisting viruses are derived from various viral families with distinct replication strategies, they all utilize common mechanisms for establishment of long-lasting infections. Here, we discuss the commonalities between persistent infections with herpes-, retro-, flavi-, arena-, and polyomaviruses that distinguish them from acutely infecting viral pathogens. These shared strategies include selection of cell subsets ideal for long-term maintenance of the viral genome, modulation of viral gene expression, viral subversion of apoptotic pathways, and avoidance of clearance by the immune system.