Intracellular bacteria are endowed with the capacity to survive and replicate inside mononuclear phagocytes (MP) and, sometimes, within certain other host cells. MP are potent effectors cells that are able to engulf and kill many bacterial invaders. Therefore, intracellular bacteria had to exploit potent evasion mechanisms that allow their survival in this hostile environment. At the early phase, natural killer cells activate antibacterial defense mechanisms. During intracellular persistence, microbial proteins are processed and presented, thus initiating T cell activation. By secreting interleukins, CD4 alpha/beta TH1 cells activate MP, converting them from a habitat to a potent effector cell; TH2-dependent activities seem to be of minor importance. Cytolytic CD8 T cells represent a further element of protection. In the case of Listeria monocytogenes, the gene products responsible for virulence and for the introduction of antigens into the MHC class I pathway are being characterized. Increasing evidence points to a role of gamma/delta T lymphocytes in antibacterial immunity, although their precise function remains to be elucidated. Protection in the host is a local event focussed on granulomatous lesions. MP accumulate at the site of microbial growth and become activated through the CD4 T cell-interleukin-MP axis. Lysis of incapacitated MP and other host cells by CD8 T cells allows release and subsequent uptake by more efficient phagocytes, thus contributing to host protection. At the same time, lysis of host cells promotes microbial dissemination and causes tissue injury, which represent pathogenic aspects of the same mechanism. Research on the immune response against intracellular bacteria not only helps us to better understand how the immune system deals with “viable antigens” in constant trans-mutation, it also forms the basis for the rational design of control measures for major health problems.