One of the functions of polyubiquitin chains is to target proteins for degradation via the 26S proteasome. Recent reports have shown that monoubiquitylation can also serve as a signal for proteolysis. Here, Ciechanover and colleagues find that proteins up to 150 amino acids long can be targeted for degradation by monoubiquitylation, whereas longer proteins need to be polyubiquitylated to become substrates for the ubiquitin–proteasome system. The authors fused a single ubiquitin residue, which in some cases was modified so that polyubiquitylation could not occur, to proteins of different lengths, including haemaglutinin repeats and truncated versions of GFP and dihydrofolate reductase. Fragments shorter than 150 residues were degraded in each case, whereas longer fragments were stable when monoubiquitylated but degraded when polyubiquitylation was allowed. Importantly, the authors showed that monoubiquitylation also targets small endogenous proteins for degradation.