Development of vaccines should be a well-trodden path in which possible diversions and roadblocks should be clearly understood. However, challenges and unexpected twists and turns are not uncommon in modern vaccine development. In this perspective the considerable uncertainties for development of third generation pertussis vaccines will be discussed along with related issues in the development of new vaccines for the prevention of serogroup B meningococcal (MenB) disease. Acellular pertussis vaccines developed in the 1980s showed good efficacy in large clinical trials and whooping cough was at historically low levels in the last decade of the 20th century in most countries where the vaccines are used. However, the unexpected resurgence in cases in several countries has questioned the ability of current acellular pertussis vaccines to provide long-term protection against the disease. For MenB vaccines the initial challenge has been to identify antigens that will induce protection against the diverse collection of isolates that cause disease. Following this there have been significant challenges to determine potential breadth of strain coverage. Furthermore, there has been a drop in the incidence of MenB disease in countries considering implementation of the new MenB vaccines making cost effectiveness a more difficult case to argue. It is likely that lessons learnt in the development and use of both pertussis and MenB vaccines will inform the future of vaccines for these two diseases. (c) 2015 Crown copyright. Journal of Chemical Technology & Biotechnology (c) 2015 Society of Chemical Industry