Schematic representation of influenza virus replication cycle and drugs currently used for prophylaxis and/or treatment of influenza, drugs in clinical trials, and those in preclinical development. Antiviral therapy predominately relies on virus-specific drugs such as the neuraminidase (NA) inhibitors (NAIs) oseltamivir and zanamivir, which bind the enzymatically active site of the NA of influenza A or B viruses and inhibit the release of budding viral particles from infected host cells. M2 inhibitors (amantadine and rimantadine) block the ion channel activity of the M2 protein of influenza A virus at the stage of virus fusion and uncoating. Drugs undergoing clinical trials in the U.S. for the prevention and treatment of influenza include Fludase (DAS181), Favipiravir (T-705), and Nitazoxanide. Sialidase inhibitor Fludase cleaves sialic acid (SA) α2,3- and SA α2,6-linked cellular receptors and inhibits virus attachment to them. Prodrug favipiravir is converted intracellularly to its active metabolite, T-705 ribofuranosyltriphosphate, which inhibits RNA polymerase activity. Nitazoxanide affects the terminal glycosylation of the hemaggluttinin (HA) glycoprotein, thereby impairing HA trafficking between the endoplasmic reticulum (ER) and the Golgi complex. The host’s immune response can be modulated by inhibitors of various cellular signaling pathways and cascades during the virus’ replication cycle. Although several inhibitors are currently in preclinical development, these investigational immunomodulatory agents can be categorized into two groups based on their target: those that target the host’s inflammatory response (left) and those that target the virus (right). Ab, antibody; COX2, cyclooxygenase-2; cRNA, complementary RNA; ERK, extracellular signaling–regulated kinase; HA, hemagglutinin; NA, neuraminidase; M2, matrix protein; MEK, MAP/ERK kinase; mRNA, viral messenger RNA; PI3K, phosphatidylinositol-3 kinase; PPAR, peroxisome proliferator-activated receptor; PKC, protein kinase C; vRNA, viral RNA.