Multiple signalling pathways that display abnormal activation patterns in gastrointestinal cancers are also essential for physiological development and homeostasis. The finely tuned balance between pathways such as Wnt, Notch, BMP, or Hedgehog is often disrupted from early stages of GI tumorigenesis, frequently leading to transcriptional modifications and subsequent alterations of proliferation and differentiation. Two examples will be presented. Firstly, we will review the role of the Hedgehog pathway in governing morphogenesis and differentiation and discuss how abnormal Hedgehog signalling is involved in gastric inflammation and cancer. We will then turn to the central role played by Sox9 both as a target and a regulator of the Wnt pathway in the intestinal epithelium and evaluate its suspected involvement in colorectal pathogenesis.