Formation of Peyer's patches requires complex interactions between the gut epithelium, the mesenchyme, and bone-marrow-derived hematopoietic progenitors. The first Peyer's patches anlage appear around embryonic day 15.5, when the endoderm has undergone transition to a simple epithelium, the lymphatic vessels have reached the intestinal mucosa, and mesenchymal cells have started to form clusters. Recent data using knockout mice provide insight into the molecular nature of the signals that mediate Peyer's patch ontogeny. These include members of the tumor-necrosis factor family and homeostatic chemokines.