A series of influenza A virus outbreaks in recent years has led to intensive interest in this highly variable zoonotic virus. Among the 12 influenza A viral proteins, non-structural protein 1 (NS1) is remarkably multifunctional, which is of great concern because of its contribution to virulence. Past and recent studies have indicated that NS1 is not only involved in the regulation of transcription and translation of the viral genome but also in a variety of virus-host interactions. New functions of NS1 are consistently being discovered. Here, we review literatures on this protein with a focus on the interplay between NS1 and host systems including host nuclear structures, post-transcription and translation systems, type I IFN system, apoptosis, inflammatory and adaptive immune responses, and the post-translational modification system. At the end of this review, we outline the most promising anti-viral drugs targeting NS1 and summarize the recent findings about the NS1 protein.