Ubiquitination, the post-translational attachment of ubiquitin or ubiquitin chains, controls the stability, interaction or activity of numerous key regulatory proteins in eukaryotic cells. At the core of the ubiquitination process is the E3 ligase, which brings ubiquitin and the target protein together, and enables the transfer of the ubiquitin to its target. The Liu lab investigates the largest family of E3 ligases, known as cullin-RING ligases (CRLs). CRLs are modular protein complexes, featuring a common cullin scaffold and an interchangeable substrate receptor that recruits specific target proteins for CRL-dependent ubiquitination and subsequent degradation. We use a variety of approaches including biochemistry, biophysics, molecular genetics, quantitative proteomics, and mathematical modeling to study how CRLs work, how their activities are regulated, and what critical roles they play in cells and organisms.