The COP9 signalosome (CSN) is an evolutionarily conserved multi-protein complex found in plants and animals. In mammals, the CSN consists of eight subunits (CSN1-CSN8). It has been suggested to play a key role in tumorigenesis, because its subunits are frequently overexpressed in human cancers and because the CSN is involved in the regulation of a number of processes that are relevant to carcinogenesis and cancer progression, e.g. cell cycle control, signal transduction, and apoptosis. The best-studied biochemical function of the CSN is the control of cellular protein stability via the ubiquitin-proteasome system through regulation of cullin-RING E3 ligase (CRL) activity by deNEDDylation of cullins or by the deubiquitination function of the CSN. Through these activities, the CSN regulates the degradation of several tumor suppressors and oncogenes that are degraded by the 26S proteasome. This review summarizes recent findings that support CSN’s role as a potential key player in tumorigenesis in general, but particularly focuses on evidence on the role of the CSN in gastrointestinal cancers. We cover links to tumorigenesis in the liver, stomach, pancreas, and colon, gathering and discussing findings about CSN’s expression and its functional impact on cancer development and progression.