Resistance to intracellular bacterial pathogens such as Brucella spp. relies on cell-mediated immunity, which involves activation of the bactericidal mechanisms of antigen-presenting cells (macrophages and dendritic cells) and the subsequent expansion of antigen-specific CD4+ and CD8+ T-cell clones. Brucella antigens induce the production of T helper type 1 (Th1) cytokines, and an adequate Th1 immune response is critical for the clearance of Brucella infection. Studies on experimental and human brucellosis indicate that interferon-gamma (IFNgamma) is the principal cytokine active against Brucella infection. On the other hand, Brucella has evolutionarily developed diverse evasion strategies to avoid the host's innate and adaptive immunity in order to establish an intracellular niche for long-term parasitism. Disturbances of the Thl response and anergy have been described in patients with chronic brucellosis, and are associated with poor outcome. Accordingly, chronic brucellosis represents a challenge for the study of immune mechanisms against Brucella and the development of novel therapeutic or vaccination approaches.