Ubiquitin-dependent proteolysis ensures that specific protein functions are turned off at the right time, in the right place, and in a unidirectional fashion. The high substrate specificity of the system is determined by a large family of ubiquitin ligases, which competes with the protein kinases to be the largest family of enzymes in mammals. Given the crucial function of the proteolytic machinery, altered degradation of cellular regulators contributes to the unchecked proliferation typical of cancer cells. Here we review the aberrant activity of a variety of ubiquitin ligases in human cancer, hence the prospect of targeting them in cancer therapy.