Brucellosis is a zoonotic disease caused by a number of Brucella species and is characterized by chronic macrophage infection. However, genes that may contribute to intracellular survival of the Brucella species are not well studied. This review presents, first, genomic islands that are present or absent in various Brucella species that may help establish Brucella infection and survival strategies. Second, the alteration in macrophage transcription by Brucella to permit its long-term survival within this hostile intracellular environment. A large number of macrophage gene transcripts are altered following Brucella infection indicating that Brucella is not a silent invader of host cells. Macrophage transcript levels associated with inflammation, apoptosis, signal transduction and vesicular intracellular trafficking are altered during Brucella infection, and likely contribute to intracellular survival of Brucella. Lastly, the host–pathogen interaction events associated with Brucella infection in living mice visualized in real-time using biophotonic imaging. Mice are often used to evaluate Brucella infections; however, Brucella dissemination and pathogenesis is poorly understood in mice. Biophotonic imaging of Brucella infections revealed sites of bacterial localization similar to human infections and different patterns of infection by attenuated or virulent Brucella.