The successful co-existence of each Brucella spp. with its preferred host is the outcome of ancient co-evolutionary relationships and selection pressures that often result in a stalemate where the pathogen has evolved to survive within the biological systems of the host, and the host has evolved innate and acquired immune systems which allow controlled survival of infection by the pathogen, ultimately supporting the survival of the host-pathogen system. In general, Brucella spp. have evolved a similar fundamental pathogenesis of facultative intracellular parasitism though the predominant route of natural exposure varies from oropharynx to genital tract, as does the preferred tissue and cellular tropism, e.g. non-professional placental trophoblasts, fetal lung, professional macrophages of reticulendothelial system, and the male and female reproductive tracts. The morphogenesis of the pyogranulomatous lesions stimulated by Brucella reflects the nature of the persistent parasitism, i.e. genome versus genome. The question is, how can this perplexing array of survival mechanisms be unraveled? Fortunately, the integration of real-time image analysis, cell biology, genome-wide analysis, proteomics and bioinformatics holds the most promise ever for the global analysis of the Brucella infectious process and the host:pathogen interface leading to a clearer understanding of the interactions of these biological systems. These discoveries will be expected to provide a frameshift in rationales for interrupting and/or controlling brucellosis at host and/or pathogen levels.