Ubiquitylation is a covalent attachment of ubiquitin to the lysine residue(s) of a protein substrate which represents an important post-translational regulation of protein activity, half-life and localization. Ubiquitination of proteins requires a multi-enzyme system comprised of ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase enzyme (E3). Ubiquitin is first activated by binding to E1 and then transferred to an E2 before covalently linked to a protein substrate in a reaction catalyzed by E3 ubiquitin ligase. Each E3 ubiquitin ligase recognizes a set of substrates and controls the specificity in ubiquitin-mediated protein degradation. Thus, targeting specific E3 ubiquitin ligases by using small molecules is a promising strategy to regulate the degradation of specific proteins.