Originally described as a destruction tag for misfolded or disused proteins ubiquitin (Ub) has recently entered centre stage in many fundamental processes like cell cycle, apoptosis, DNA repair or endocytosis. In these processes Ub acts as a signalling component able to trigger molecular events in cells. Ub does so by operating as a reversible and highly versatile regulatory signal for an expanding number of Ub-binding domains (UBD) present in cellular proteins that convey Ub signals into appropriate cellular phenotypes. In addition, it is becoming apparent that deregulation of Ub pathways results in the development of human diseases including many types of tumours. The common principles and specific features of Ub and other Ub-like modifiers and their binding domains in the regulation of signaling pathways will be discussed.