In the search for new anti-influenza agents, the viral polymerase has often been targeted due to the involvement of multiple conserved proteins and their distinct activities. Polymerase associates with each of the eight singled-stranded negative-sense viral RNA segments. These transcriptionally competent segments are coated with multiple copies of nucleoprotein (NP) to form the ribonucleoprotein. NP is an abundant essential protein, possessing operative and structural functions, and participating in genome organization, nuclear trafficking and RNA transcription and replication. This review examines the NP structure and function, and explores NP as an emerging target for anti-influenza drug development, focusing on recently discovered aryl piperazine amide inhibitor chemotypes.