Meningococcal disease is mainly caused by serogroup B in many West European countries. Recently, a highly efficacious vaccine against infections caused by serogroup C has been introduced in the UK and The Netherlands. However, an effective vaccine against serogroup B has not yet become available. Outer membrane vesicle vaccines against serogroup B were previously tested in large Phase III trials but showed a low efficacy in young children. In addition, the high variability of the vaccines' main component, porin A, potentially diminishes its efficacy. Therefore, several approaches in either optimizing these outer membrane vesicle vaccines or searching for novel, highly conserved antigens are currently under investigation. The sequencing of the meningococcal genome has provided new opportunities to detect additional immunogenic epitopes. In this review, the developments in the search for a broadly protective meningococcal serogroup B vaccine will be discussed.