Ubiquitin (Ub) is a small protein modifier involved in cellular functions such as cell cycle, apoptosis, cell signalling, endocytosis, transcription and DNA repair. Ubiquitin operates as a reversible and highly versatile regulatory signal, which may be read and interpreted by an expanding number of Ub-binding domains (UBD). There is accumulating evidence that mutations or altered expression of ubiquitylating or de-ubiquitylating enzymes as well as of Ub-binding proteins affect crucial mediators of such functions and are found in several malignancies. Here we discuss how oncogenic alterations in the Ub system can be targeted by anti-cancer therapies.