A surprisingly large and unrelated number of human tumors depend on sustained HEDGEHOG-GLI (HH-GLI) signaling for growth. This includes cancers of the skin, brain, colon, lungs, prostate, blood and pancreas among others. The basis of such commonality is not obvious. HH-GLI signaling has also been shown to be active in and required for cancer stem cell survival and expansion in different cancer types, and its activity is essential not only for tumor growth but also for recurrence and metastatic growth, two key medical problems. Here we review recent data on the role of HH-GLI signaling in cancer focusing on the role of the GLI code, the regulated combinatorial and cooperative function of repressive and activating forms of all Gli transcription factors, as a signaling nexus that integrates not only HH signals but also those of multiple tumor suppressors and oncogenes. Recent data support the view that the context-dependent regulation of the GLI code by oncogenes and tumor suppressors constitutes a basis for the widespread involvement of GLI1 in human cancers, representing a perversion of its normal role in the control of stem cell lineages during normal development and homeostasis.