Human infection with the highly pathogenic avian influenza A virus H5N1 is associated with a high mortality and morbidity. H5N1 continues to transmit from poultry to the human population, raising serious concerns about its pandemic potential. Current influenza H5N1 vaccines are based upon the elicitation of a neutralizing antibody (Ab) response against the major epitope regions of the viral surface glycoprotein, hemagglutinin (HA). However, antigenic drift mutations in immune-dominant regions on the HA structure allow the virus to escape Ab neutralization. Epitope mapping using neutralizing monoclonal antibodies (mAb) helps define mechanisms of antigenic drift, neutralizing escape and can facilitate pre-pandemic vaccine design. This review explores the current knowledge base of the antigenic sites of the H5N1 HA molecule. The relationship between the epitope architecture of the H5N1 HA, antigenic evolution of the different H5N1 lineages and the antigenic complexity of the H5N1 virus lineages that constitute potential pandemic strains are discussed in detail.