Evidence has shown that quadrivalent influenza vaccines containing all four subtypes are safe and immunogenic. However, to date there have been few published studies exploring the population-level clinical and economic impact of quadrivalent compared to trivalent influenza vaccines. Economic evaluation studies need to be conducted in order to inform country-level decision making about whether (and how to) introduce and replace the current trivalent influenza vaccines with quadrivalent influenza vaccination programs. Several key issues associated with estimating the clinical and economic impact of the trivalent versus quadrivalent vaccines are discussed in this article, particularly the complexities involved in estimating the incremental preventable disease and economic burden. Other factors, such as the indirect (herd) protection from quadrivalent influenza vaccination and the timing of the replacement of trivalent influenza vaccination programs are also discussed.