Clinical trials of vaccines differ from those of drugs both practically and ethically. Influenza vaccine trials pose additional challenges which flow from the seasonality of the disease and vaccine programmes and the changeability of circulating strains and epidemic size. Serological correlates are widely used in evaluating influenza vaccines but interpreting such responses is also difficult. Development and testing of vaccines for deployment in an influenza pandemic combines all these obstacles with extreme unpredictability, enormous urgency and the need for very large numbers of doses. Advances in manufacturing technology, diagnostics, identification of stable protective antigens and epitopes, new adjuvants and improved understanding of indirect and downstream effects may help to alleviate these difficulties in the future.