The development and differentiation of the gastric mucosa are controlled by a complex interplay of signaling proteins and transcriptional regulators. This process is complicated by the fact that the stomach is derived from two germ layers, the endoderm and the mesoderm, with the first giving rise to the mature epithelium and the latter contributing the smooth muscle required for peristalsis. Reciprocal epithelial-mesenchymal interactions dictate the formation of the stomach during fetal development, and also contribute to its continuous regeneration and differentiation throughout adult life. In this chapter, we discuss the discoveries that have been made in different model systems, from zebrafish to human, which show that the Hedgehog, Wnt, Notch, bone morphogenetic protein, and fibroblast growth factor (FGF) signaling systems play essential roles during various stages of stomach development.