Meningococcal disease is a 200-year-old problem that has proved hard to crack. It mostly affects children and young adults and can cause death or serious permanent injury within hours. It can be sporadic, epidemic, or pandemic. Since 1988 we have employed a natural history and population genomics-based approach to investigate two meningococcal enigmas: First, why does the bacterium cause disease at all; and second, why is it so very variable in its ability to cause disease, its genes, and its antigens. We have applied the answers to these questions to disease control by vaccination. Continued advances in sequencing technologies have enabled us to catalogue meningococcal population variation exhaustively, from individual genes to the whole genome, developing techniques on the way, such as MLST (www.pubmlst.org), that became universally used. By realising the importance of the interaction of meningococcal population structure and antigenic variation, we demonstrated the importance of herd immunity, initially with serogroup C conjugate polysaccharide vaccines in the UK from 1999 to 2001, and then with the introduction of a similar serogroup A vaccine in Africa in 2010. This has supported better targeted vaccine introductions, including the use of the serogroup ACWY vaccine in teenagers in the UK in 2015. The lack of serogroup B polysaccharide vaccines remains problematic, with recently introduced protein-based vaccines challenged by antigen variability combined with uncertain herd immunity effects. Consequently, on-going cataloguing of antigenic diversity and data sharing remain essential. In conclusion, the report card is mixed: ‘some good progress but could do better’.