Antigenic variation in influenza viruses primarily involves the hemagglutinin (HA) and neuraminidase glycoproteins of the virus membranes. The HAs of the viruses involved in the two late 19th century antigenic shifts may also have belonged to the H2 and H3 subtypes, but the significance of this apparent restriction is not known. Antigenic drift describes the progressive change in antigenic properties which occurs with time after the introduction of a new subtype into the human population. The changes in HA antigenicity are analyzed in hemagglutination inhibition tests using convalescent ferret antisera which are highly strain specific and show clearly the relationships between viruses isolated in different years. The antigenic significance of changes in these five regions is confirmed by observations that single amino acid substitutions in one or other of the sites are detected in the HAs of monoclonal antibody selected antigenic variants.