Antigenic variability of immunodominant antigens is a common mechanism used by pathogens to escape the immune response. Frequently, the proposed solution is a universal vaccine based on conserved antigens present on all strains of the pathogen. Indeed, a lot of progress has been made in the development of vaccines that induce broad immune responses. However, truly universal vaccines are not easy to produce and still face many challenges, mostly because in those pathogens that use antigenic variability to escape the immune response, conserved antigens have been selected by evolution to be poorly immunogenic. This review describes the progress made towards the development of vaccines inducing broad protection against Neisseria meningitidis, influenza, HIV, and Candida and the challenges of developing truly universal vaccines.