Publisher Summary This chapter discusses immunology of influenza virus infections, limitations of current vaccines, and approaches for developing highly effective influenza virus vaccines. Influenza viruses are negative-strand RNA viruses that are surrounded by an envelope, spiked by surface glycoproteins with hemagglutinin (HA) or neuraminidase (NA) activity. Influenza virus infection is generally accompanied by fever, systemic symptoms, and respiratory tract illnesses, such as rhinitis, pharyngitis, tracheobronchitis, and in children, croup and bronchiolitis. Licensed influenza vaccines consist of formalin-inactivated whole influenza A and influenza B viruses or subunit vaccines consisting of chemically treated split viruses formulated with alum. The current inactivated vaccines, given by intramuscular or subcutaneous injection, achieve a reasonable degree of protection against naturally occurring disease among normal healthy adults when the antigens of the vaccine and those of the circulating influenza viruses are closely related. However, when given annually, the resistance induced in healthy persons is incomplete and short-lived.