Brucella is an intracellular pathogen that survives and multiplies inside host macrophages to cause brucellosis. The underlying mechanisms of intracellular survival, including the bacterial and the host determinants remain relatively unknown. Recent advances have helped to decipher how Brucella controls the biogenesis of its intramacrophagic replicative organelle. Brucella initially avoids or escapes the endocytic pathway to ensure its intracellular survival, which is then further secured via the biogenesis of an endoplasmic reticulum-derived replicative organelle. A major virulence factor, the VirB type IV secretion system, is required for sustained interactions and fusion with the host endoplasmic reticulum.