Conventional egg-based manufacturing technology for seasonal influenza vaccines has several drawbacks, including its inflexibility, reliance on egg supplies, risk of contamination, absence of growth of some isolates and egg-adaptive viral mutations that threaten vaccine matching. To overcome these limitations, cell culture-derived vaccines have been designed, including the trivalent inactivated vaccine Flucelvax®/Optaflu® (brand names in the US/EU, respectively). Flucelvax®/Optaflu® has gained wide regulatory approval and is currently implemented in several countries. Non-clinical studies have assuaged hypothetical concerns regarding oncogenicity and use in persons allergic to dogs. Ample clinical data suggest the non-inferiority of Flucelvax®/Optaflu® to egg-based vaccines in terms of immunogenicity, safety and tolerability, and it has fulfilled American and European mandatory requirements. Although Flucelvax®/Optaflu® is currently indicated only for adults and the elderly, pediatric data indicate its good immunogenicity and safety. This paper provides an update on the clinical development of Flucelvax®/Optaflu®, its seasonal trials and available post-marketing surveillance data.