Retroviruses are known to exhibit remarkable genomic pliancy, a capacity that has been attributed to one or more error prone steps in the viral replication cycle. However, increasing evidence suggests that such error represents a key element in viral survival, as exemplified by studies on virus immune evasion, shifts of cellular tropism, and anatomic compartmentalization, which facilitate persistent virus reservoirs. Understanding the dynamic mechanisms that contribute to the establishment and maintenance of retroviral persistence is critical toward the goal of attaining HIV-1 eradication.