The 20th century witnessed three global influenza pandemics: in 1918, 1957, and 1968. These pandemics, identified as Spanish, Asian, and Hong Kong influenza, respectively, are now known to represent different antigenic subtypes of influenza A virus: H1N1, H2N2, and H3N2. The 1957 and 1968 pandemics, occurring during the era of modern virology, showed significant changes in the hemagglutinin (HA) antigen of the causative viruses compared to their antecedent strains. The 1918 pandemic's origin remains uncertain, but evidence suggests it may have originated in swine, spreading to humans. The 1957 pandemic, caused by H2N2, was the first to be studied in detail, revealing its high virulence and the importance of bacterial co-infection in mortality. The 1968 pandemic, caused by H3N2, was characterized by a "smoldering" nature, with varying impact across regions due to pre-existing immunity. The 1947 pseudopandemic and the 1976 abortive pandemic highlighted the unpredictable nature of influenza, with the latter involving a genetic reassortant virus that failed to cause a full-blown pandemic. The article emphasizes the need for preparedness, particularly through the development of high-yield reassortant viruses for potential vaccine production, to address the unpredictable nature of future pandemics.The 20th century witnessed three global influenza pandemics: in 1918, 1957, and 1968. These pandemics, identified as Spanish, Asian, and Hong Kong influenza, respectively, are now known to represent different antigenic subtypes of influenza A virus: H1N1, H2N2, and H3N2. The 1957 and 1968 pandemics, occurring during the era of modern virology, showed significant changes in the hemagglutinin (HA) antigen of the causative viruses compared to their antecedent strains. The 1918 pandemic's origin remains uncertain, but evidence suggests it may have originated in swine, spreading to humans. The 1957 pandemic, caused by H2N2, was the first to be studied in detail, revealing its high virulence and the importance of bacterial co-infection in mortality. The 1968 pandemic, caused by H3N2, was characterized by a "smoldering" nature, with varying impact across regions due to pre-existing immunity. The 1947 pseudopandemic and the 1976 abortive pandemic highlighted the unpredictable nature of influenza, with the latter involving a genetic reassortant virus that failed to cause a full-blown pandemic. The article emphasizes the need for preparedness, particularly through the development of high-yield reassortant viruses for potential vaccine production, to address the unpredictable nature of future pandemics.