The first species of Brucella was isolated and characterized almost 120 years ago and recently the complete nucleotide sequences of the genomes of a number of well-characterized Brucella strains have been determined. However, compared to other bacterial pathogens relatively little is known about the factors contributing to its persistence in the host and multiplication within phagocytic cells. Also, many aspects of interaction between Brucella and their host remain unclear. Molecular characterization of intracellular survival process of Brucella is important as it will provide guidance for prevention and control. One of the features that distinguish Brucella is that they do not express classical virulence factors. Thus identification of virulence factors has been elusive and some of the identifications are putative. Disruption of putative virulence genes and studying their effect on attenuation in cell lines or mouse models is a widely used method. However, in most cases it is not apparent whether the mutated genes encode virulence factors or merely affect metabolic pathways of the pathogen. In addition, some mutations in Brucella can be compensated by redundancy or backup mechanisms. This review will examine known virulence genes (real and putative) identified to date and the mechanisms that contribute to the intracellular survival of Brucella and its ability to establish chronic infection.