Unlike proteins tagged with Lys48-linked ubiquitin, Lys63-polyubiquitylated proteins are directed to the lysosome rather than the proteasome. Because they do bind the proteasome in vitro, the authors postulated that other factors may prevent this interaction in vivo. Indeed, they show that ESCRT-0 components preferentially bind to proteins tagged with four or more Lys63-linked ubiquitin molecules and that reduction of ESCRT-0 levels increases binding of Lys63-tagged proteins to the proteasome in cells. Interestingly, Lys48-ubiquitylated proteins were specifically bound by RAD23, and this promoted their association with the proteasome. So, these ubiquitin-binding proteins determine whether a protein is targeted to the proteasome for degradation or to the endosome–lysosome pathway.