The propensity of influenza virus to develop resistance to commonly prescribed drugs highlights the need for continuing development of new therapeutics. Biological and structural investigations of the enzymatic and interaction domains among influenza A virus polymerase subunits have broadened the target reservoir for drug screening. With the wealth of knowledge from these studies, identification of small-molecule and peptidic inhibitors that specifically abrogate polymerase activity or disrupt the polymerase assembly has emerged as an innovative and promising approach. Importantly, those domains are highly conserved among influenza subtypes and thus minimize the emergence of drug resistant mutants. An overview of the reported enzymatic inhibitors and protein-protein disruptors has been provided, in our effort to facilitate the development of next-generation anti-influenza therapeutics.