Parasitic protozoa of the genus Leishmania have provided a useful perspective for immunologists in terms of host defense mechanisms critical for the resolution of infection caused by intracellular pathogens. These organisms, which normally reside in a late endosomal, major histocompatibility complex (MHC) class II(+) compartment within host macrophages cells, require CD4(+) T-cell responses for the control of disease. The paradigm for the CD4(+) T-helper 1 (Th1)/Th2 dichotomy is largely based on the curing/non-curing responses, respectively, to Leishmania major infection. However, this genus of parasitic protozoa is evolutionarily diverse, with the cutaneous disease-causing organisms of the Old World (L. major) and New World (Leishmania mexicana/ Leishmania amazonensis) having diverged 40-80 million years ago. Further adaptations to survive within the visceral organs (for Leishmania donovani, Leishmania chagasi, and Leishmania infantum) must have been required. Consequently, significant differences in host-parasite interactions have evolved. Different virulence factors have been identified for distinct Leishmania species, and there are profound differences in the immune mechanisms that mediate susceptibility/resistance to infection and in the pathology associated with disease. These variations not only point to interesting features of the host-pathogen interaction and immunobiology of this genus of parasitic protozoa, but also have important implications for immunotherapy and vaccine development.