The regulated degradation of cellular proteins by the ubiquitin-proteasome system impacts a range of vital cellular processes in both normal and cancerous cells. An ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3) catalyzes the conjugation of the protein ubiquitin to a target protein and, thereby, tags that protein for recognition and destruction by the proteasome. Ubiquitin ligases are particularly interesting because they determine substrate selection. This review examines the role of dysregulated ubiquitin ligase activity in the development and progression of various cancers, and highlights why ubiquitin ligases have emerged as extremely attractive targets for therapeutic intervention in a number of human malignancies.