Ubiquitylation ? the conjugation of proteins with a small protein called ubiquitin ? touches upon all aspects of eukaryotic biology, and its defective regulation is manifest in diseases that range from developmental abnormalities and autoimmunity to neurodegenerative diseases and cancer. A few years ago, we could only have dreamt of the complex arsenal of enzymes dedicated to ubiquitylation. Why has nature come up with so many ways of doing what seems to be such a simple job?