Defective interfering particles (DIPs) were first described by Preben von Magnus as a non-infectious form of influenza virus arising due to undiluted passages of the virus in embryonated eggs. DIPs are characterized by internal deletions in the viral genome, interference with the standard virus replication, attenuation of cytopathic effects and viral persistence. Even though DIP-mediated virus interference and host cell persistence have been reported with both experimental and natural infections, the processes involved in modifying or influencing the fate of a viral infection are poorly understood. In this review, the properties of DIPs, the mechanisms involved in interference and viral persistence in modulation of disease outcomes and their possibilities towards an antiviral approach have been highlighted.