Macrophages, tissue-based phagocytic cells derived from blood monocytes, play important roles in immunity and homeostasis. As professional scavengers, macrophages phagocytose microbes, apoptotic and necrotic cells and take up modified lipoprotein particles. However, many of their complex interactions with other immune cells and/or various ligands are not yet clearly understood. To identify and isolate macrophage cell surface molecules, particularly macrophage receptors, for which ligands are known, a powerful generalized screening method has been established. As discussed in this chapter, this technique based on function has been successfully applied for the identification of dectin-1, the major macrophage receptor involved in the binding and recognition of beta-glucans (Nature 413:36-37, 2001).