Avian influenza A viruses, such as the highly pathogenic avian H5N1 viruses, sporadically enter into the human population but often do not transmit between individuals. In rare cases, however, they establish a new virus lineage in humans. In addition to well-characterized barriers to cell entry, one major hurdle which avian viruses must overcome is their poor polymerase activity in human cells. There is compelling evidence that these viruses overcome this obstacle by acquiring adaptive mutations in the polymerase subunits PB1, PB2 and PA and the nucleoprotein NP, as well as in the novel polymerase co-factor NEP. Recent findings suggest that synthesis of the viral genome may represent the major defect of avian polymerases in human cells. While the precise mechanisms remain to be unveiled, it appears that a broad spectrum of polymerase adaptive mutations can act collectively to overcome this defect. Thus, identification and monitoring of emerging adaptive mutations that further increase polymerase activity in human cells is critical to estimate the pandemic potential of avian viruses.