Influenza will always be a threat to human health in one form or another. Yet despite the long shared history of humans and influenza, there are still many fundamental areas that we know relatively little about. These include understanding what drives the evolution and spread of influenza viruses from year to year, and anticipating what might happen when new epidemic and pandemic strains enter human populations. New technologies such as next generation sequencing provide powerful new tools for understanding this. Within human populations, antigenic drift is driven by host immune responses that push the generation of immune escape variants. Recent data suggests that this may not be as unpredictable as thought, and that clues to future epidemic strains may be found within currently infected individuals. It is also possible to identify previously unrecognized spread, which should lead to a better understanding of which viruses will cause our season and how long they have been present before the “season” is recognized. Armed with this information then it is possible to begin sorting out the complex factors that determine where our seasonal influenza viruses come from, when they truly begin circulating, whether they persist between seasons, the effect of increasing travel (tourists and FIFO workers) on the spread of influenza, and the importance of the different seasonal patterns in our tropical and sub-tropical areas. This has obvious applications to better controlling inter-pandemic influenza, as well as better detecting the entry and spread of new pandemic strains.