The pathogenesis mechanism and the identity of major virulence factors of the highly infectious human pathogen F. tularensis tularensis, are still poorly characterized. The restricted efficacy of the sole available vaccine (the LVS attenuated strain) and residual toxicity has motivated extensive R&D efforts directed toward the identification of alternative tularemia vaccine formulations based on attenuated mutants, subunit vaccines and T-cell epitope-based vaccines. Identification of vaccine candidates by bioinformatic approaches is mostly driven by the availability of genome sequence data for numerous human-virulent as well as avirulent strains. In an attempt to select for F. tularensis Schu S4 potent antigens, we have developed a strategy based on genome-scale in silico analyses and data mining of published global experimental studies. The compiled information was divided into distinct biologically relevant categories. Protocols for qualitative and quantitative scoring for each of the categories, were developed. Together with implementation of a biological rationale, these served for ranking and prioritization of the putative antigens, providing a basis for subsequent selection of the top-ranking candidates to be evaluated experimentally.