The ubiquitin-proteasome system fulfills an essential function in eukaryotes by controlling the levels of crucial intracellular regulatory proteins. In this system, a specific type of polyubiquitin chain acts as the proximal signal for targeting substrates to 26S proteasomes for degradation. Recent results have revealed important determinants of polyubiquitin-chain recognition by proteasomes, helping to explain the biological rationale behind this novel signaling mechanism.