The emergence and global spread of the 2009 pandemic H1N1 influenza virus reminds us that we are limited in the strategies available to control influenza infection. Vaccines are the best option for the prophylaxis and control of a pandemic; however the lag time between virus identification and vaccine distribution exceeds six months and concerns of vaccine safety are a growing issue leading to vaccination refusal. In the short term, antiviral therapy is vital to control the spread of influenza; however, we are currently limited to four licensed anti-influenza drugs: the neuraminidase (NA) inhibitors oseltamivir and zanamivir, and M2 ion-channel inhibitors amantadine and rimantadine. The value of NA inhibitors was clearly established during the initial phases of the 2009 pandemic when vaccines were not available, i.e. stockpiles of antivirals are valuable. Unfortunately, as drug-resistant variants continue to emerge naturally and through selective pressure applied by use of antiviral drugs, the efficacy of these drugs declines. Because we cannot predict the strain of influenza virus that will cause the next epidemic or pandemic, it is important that we develop novel anti-influenza drugs with broad reactivity against all strains and subtypes and consider moving to multiple drug therapy in the future. Here we review the experimental data on investigational antiviral agents undergoing clinical trials [parenteral zanamivir and peramivir; long acting NA inhibitors (LANI), and polymerase inhibitor T-705], experimental antiviral agents that target either the virus [hemagglutinin (HA) inhibitor Cyanovirin-N and Thiazolides] or the host [fusion protein inhibitor (DAS181), Cox-2 inhibitors and PPAR agonists].