The role of myelomonocytic cells like monocytes and macrophages as first line of host defense is well established. Recent understanding of these cells using systems biology, transgenesis and in disease models has brought them to a center stage in orchestrating crucial functions during homeostasis and pathogenesis. Thus, understanding the functional diversity of these cells in health and disease as well as the mechanisms that control these events would be crucial for designing strategies for regulating disease and reinstate homeostasis.