Most viruses express one or several proteins that counter the antiviral defences of the host-cell. In influenza viruses, non-structural protein NS1 holds this task. Absent from the viral particle but highly expressed in the infected cell, NS1 dramatically inhibits the cellular gene expression and prevents the activation of key players in the interferon system. In addition, NS1 selectively enhances the translation of viral mRNAs and may regulate the synthesis of viral RNAs. Our knowledge of the virus and of its protein NS1 has dramatically increased during the last 15 years. The atomic structure of NS1 has been determined, many cellular partners were identified and its multiple activities have been studied in depth. This review presents our current knowledge and attempts to establish relationships between the structure, the ligands, the activities of NS1 and the pathogenicity of the virus. A better knowledge of NS1 could help in elaborating novel antiviral strategies, based on either live vaccines with altered NS1 or on new small-molecule inhibitors of NS1.