Macrophages are the first line of defense of the organism against pathogens and, in response to the microenvironment, become differentially activated. In the presence of IL-4 and IL-13, cytokines that are produced in a Th-2 type response, particularly during allergy and parasitic infections, macrophages become differentially activated. Alternative activated macrophages play an important role in the protection of the host by decreasing inflammation and promoting tissues repair. However, alternative activation of macrophages also downregulates host protection against selected pathogens. This defect is associated with an altered receptor expression pattern and extensive modulation of intracellular membrane trafficking. This review shows how alternative activation of macrophages induces extensive cellular remodelling of phagocytic, endocytic, signaling and secretory pathways which play an important, but unclear role in the pathogenesis of different disease.