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This Special Issue of Cell Death & Differentiation is dedicated to ubiquitination, one of the most complex and pervasive post-translational protein modifications that affects thousands of targets and all aspects of eukaryotic biology. In this set of commissioned articles, the authors discuss new players of the complex ubiquitin system, the role of new 'ciphers' of the ubiquitin code, and emerging concepts of ubiquitin-mediated processes in cell physiology and disease development. Read through to learn how targeting components of the ubiquitin machinery could translate into new therapeutic opportunities.