African trypanosomes are pathogens for humans and livestock. They are single-cell, extra-cellular parasites that cause persistent infections of the blood and induce profound immunosuppression. Here, we review recent work on experimental African trypanosomiasis, especially infections with Trypanosoma congolense, in mice with regard to mechanisms of immunosuppression and immunopathology. The center of the immunopathology is the T-cell-independent production of antibodies to the variant surface glycoprotein (VSG) of trypanosomes, the anti-VSG antibody-mediated phagocytosis of trypanosomes by macrophages, and the subsequent profound dysregulation of the macrophage system. Depending on the genetics of the host and the parasite load, the malfunction of the macrophage system is enhanced by interferon-gamma produced by parasite-specific, major histocompatibility complex class II-restricted, matrix-adherent CD4(+) T cells or downregulated by interleuin-10 produced by parasite-specific, CD4(+)CD25(high) Forkhead box protein 3(+) regulatory T cells. There is a physiological conflict of the two relevant cytokines interleukin-10 and interferon-gamma in regulating the immunopathology versus regulating the induction and effect of protective immune responses. On the basis of very recent work in our laboratory, we propose a hypothetical model suggesting a cross-regulation of natural killer T cells and CD4(+)CD25(high) Forkhead box protein 3(+) regulatory T cells in experimental infections with T. congolense.