The ubiquitin-proteasome system (UPS) is a major proteolytic system that regulates the degradation of intracellular proteins in the heart. The UPS regulates the turnover of misfolded and damaged proteins, in addition to numerous cellular processes, by affecting the stability of short-lived proteins such as transcription factors and cell signaling pathways. The UPS is tightly regulated by the specificity of ubiquitin ligases that recognize specific substrates and direct the addition of ubiquitin, targeting the substrates for degradation by the 26S proteasome. An increasing number of cardiac ubiquitin ligases have been identified, and the number of substrates each one is known to recognize also has increased, expanding their roles. Although mainly cardioprotective roles have been attributed to ubiquitin ligases, new studies have identified exceptions to this rule. This review discusses the mechanisms of cardiac ubiquitin ligases and identifies their role in common cardiac diseases including cardiac hypertrophy, cardiac atrophy, ischemic heart disease, and diabetic cardiomyopathy.