Amantadine is a specific anti-influenza A drug that inhibits viral replication by binding to the M2 channel and preventing proton conductance. The increasing resistance to amantadine in strains of the influenza A virus that infect both animals and humans has been highlighted frequently. Resistance is usually caused by one of several single mutations in the M2 channel, but variants with double mutations have also been reported. Attempts to develop alternative inhibitors of the M2 channel that are effective against the resistant mutants have been unsuccessful, mainly because of the lack of information on the precise mode of inhibitor binding. This review summarizes the advances made in determining the mechanisms of action of amantadine and the development of novel inhibitors of the M2 channel during the past 2 years.