Viral infection in animals and plants is a serious problem worldwide. It causes dramatic losses in health and economy. Many approaches to combat with viral infectious diseases have been intensively investigated. Measures taken against viral infections can either aim for protecting from viral infection or eliminating the viruses after infection. RNA dependent RNA polymerase (RdRp) is a key enzyme for viral replication and found in all positive strand RNA viruses. Disturbing the RdRp activity therefore results in reducing or inhibiting the virus infection. In this review we focus on reviewing different strategies and agents to inhibit the RdRps of different mammalian and plant positive-sense (ss) RNA viruses. The strategies described in this review are mainly focusing on interference of the nucleotides which are the substrates need for RdRp and blocking the RdRp itself by using chemical agents or antibodies specifically binding to the different domains of the RdRps. Moreover using small interfering (si) RNA technology platform to inhibit the RdRp activity is also discussed.