Ontogeny and differentiation of cells of the monocyte/macrophage lineage are currently subjects of intense research. The concept of the macrophage as “simple” phagocytic cell has undergone profound changes. It has now been established that this myeloid lineage of cells is phenotypically and functionally much more diverse and exerts a much wider influence on the immune response than previously thought. How have these new findings changed our perception of the role of monocytes and macrophages in parasitic diseases? There is now strong evidence that macrophages fulfill organ-specific differential functions, exert activating as well as inhibitory effects on the adaptive immune response, and exist in a whole range of different activation statuses which show a high degree of plasticity. In the present chapter, we will not only review the pertinent literature on these new developments but also bring it into relation to the anti-infectious immune response, focusing on four parasitic diseases (trypanosomiasis, toxoplasmosis, malaria, and leishmaniasis) as examples.