Influenza A surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), are the major targets of neutralizing antibodies which necessitate their inclusion in influenza vaccines. The frequent antigenic drift and shift of these proteins are responsible for the annual epidemics and occasional pandemics of influenza. Therefore, vaccines must be reformulated annually to include the HA and NA proteins of the viral strains predicted for the upcoming flu season. There are inherent limitations in the annual vaccine preparation process since testing for effectiveness, approval by regulatory agencies and distribution of these vaccines can take approximately 6 months. These drawbacks are most pronounced in situations of pandemic influenza such as the recent swine-origin 2009 H1N1 pandemic, thus there is a critical need for the development of new antiviral and vaccine strategies. One promising new area of research is targeting the conserved regions of influenza surface glycoproteins. Recent studies have demonstrated that vaccines based on highly conserved sequences or antibodies raised against conserved epitopes can protect animals against diverse influenza A virus subtypes. In this review, we focus on the challenges associated with the two main surface glycoproteins, HA and NA, while emphasizing recent advances in bioinformatics tools and their contribution to the design of new diagnostics, vaccines and antivirals.