New vaccine technology has led to vaccines containing highly purified antigens with improved safety profiles, but increased antigen purity often results in weakened immunogenicity. A better understanding of innate and adaptive immunity and their interaction at the molecular level has led to the use of innovative adjuvants combined with careful antigen selection. Adjuvants can be used to amplify the immune response, and the combination of antigens with more than one adjuvant, the Adjuvant System approach, allows the development of vaccines which generate specific and effective immune responses adapted to both the pathogen and the target population. One of those Adjuvant Systems is AS04, a combination of the TLR4 agonist MPL (3-O-desacyl-4-monophosphoryl lipid A) and aluminum salt. The added value of MPL in AS04-based formulation above Aluminium was evidenced for a prophylactic human papillomavirus (HPV)-16/18 vaccine by higher vaccine-elicited antibody responses, as well as the induction of higher levels of memory B-cells. This review focuses on the role of AS04 for development of Cervarix™, a vaccine for the prevention of cervical cancer.