Our understanding of how ubiquitin regulates cellular functions has greatly expanded in the past several years, spurred by discoveries of protein families involved in ubiquitin conjugation and deconjugation, and of nonproteasomal signaling functions for ubiquitin and ubiquitin-related proteins. The first Keystone meeting on Ubiquitin and Signalling, in February 2005, was highly successful, based on both strong attendance and feedback from the participants. The significance and timely nature of the ubiquitination problem is highlighted by the 2004 Nobel Prize in Chemistry honoring pioneers in the field. We anticipate a further explosion in our understanding of ubiquitination over the next few years, and propose a meeting that captures this momentum. Ubiquitin regulates an enormous range of cellular processes. There are almost as many predicted human ubiquitin ligases as protein kinases, and the ubiquitin system has been directly implicated in numerous diseases, including many cancers and neurodegenerative disorders. Many protein domains have recently been associated with ubiquitination, deubiquitination or ubiquitin binding. These are found in several thousand proteins, presenting the challenge to determine their functions and mechanistic links to the ubiquitin system. In addition, the ubiquitin system is now widely recognized as a target for pharmacological intervention in various diseases. The goal of the meeting is to bring together experts from different areas of ubiquitin research as well as experts from other fields that are beginning to be affected by our knowledge of ubiquitin function. We expect that this meeting will foster extensive discussion of ubiquitin system function in both normal and pathological states.