African trypanosomes can cause prolonged chronic infections through a mechanism of antigen variation whereby they manipulate the humoral immune system of their hosts. However, besides antigenic variation these extracellular parasites exert other immunoregulatory activities mainly mediated by innate cells in particular macrophage-like (M) cells. In this review, the modulation of M cells through parasite factors and host cytokines as well as their role in parasite control and immunopathology will be examined. The concept of M cell polarization into distinct activation states (M1, M2) that may contribute to trypanosusceptibility or resistance will be discussed. Finally, the possibility to interfere with such activation states hereby providing new therapeutical modalities in the treatment of this infectious disease will be illustrated.