The attachment of ubiquitin and ubiquitin chains are critical post-translational modifications. Diseases, like cancer, often involve dysregulation of this ubiquitin system. Here, we report the discovery of small, highly non-proteinogenic cyclic peptides which can tightly bind and modulate ubiquitin chains with particular Lys48-linkages. Our cyclic peptides block the action of deubiquitinases and the proteasome, induce apoptosis in vitro, and attenuate tumor growth in vivo. We conclude that modulating ubiquitin chains is a promising avenue for future anti-cancer therapeutics.