One of the major challenges in vaccine development is the identification of microbial components that give rise to a protective immune response. Over the last decade, genome and proteome-based methods have proven successful in discovering new vaccine candidates for many pathogens through the selection of secreted or surface-exposed protein antigens and their screening in proper biological assays. However, these approaches still require intensive research activities to single out, among the large number of secreted and surface exposed proteins those very few which are protective. The question of which structural properties render an antigen capable of eliciting the production of functional remains most challenging. In such scientific and methodological context, the EU-funded project BacAbs was set up in 2007 with the main objective of developing a knowledge-based protocol able to discern protective from non-protective protein antigens, based on their amino acid sequences and molecular properties. The successful BacAbs multidisciplinary approach is highlighted by the recent analysis of three antigens from two diverse pathogens. Here, we describe the work and results carried out so far by the BacAbs Consortium, and discuss its relevance with regards to accelerating antigen selection processes and state-of-the-art vaccine development.