Assembly of the cell surface IL-10 receptor complex is the first step in initiating IL-10 signaling pathways that regulate intestinal inflammation, viral persistence and even tumor surveillance. The discovery of IL-10 homologs in the genomes of herpes viruses suggests IL-10 signaling pathways can be manipulated at the level of the receptor complex. This chapter will describe our current molecular understanding of IL-10 receptor assembly based on crystal structures and biochemical analyses of cellular and viral IL-10 receptor complexes.