E3 ubiquitin ligases are a large family of proteins that catalyse the ubiquitination of many proteins for degradation by the 26S proteasome. E3 ubiquitin ligases play pivotal roles in the process of insulin resistance and diabetes. In this review, we summarize the currently available studies to analyse the potential role of E3 ubiquitin ligases in the development of insulin resistance. We propose two mechanisms by which E3 ubiquitin ligases can affect the process of insulin resistance. First, E3 ubiquitin ligases directly degrade the insulin receptor, insulin receptor substrate and other key insulin signalling molecules via the UPS . Second, E3 ubiquitin ligases indirectly regulate insulin signalling by regulating pro‐inflammatory mediators that are involved in the regulation of insulin signalling molecules, such as tumour necrosis factor‐α, interleukin ( IL )‐6, IL ‐4, IL ‐13, IL ‐1β, monocyte chemoattractant protein‐1 and hypoxia‐inducible factor 1α. Determining the mechanism by which E3 ubiquitin ligases affect the development of insulin resistance can identify a novel strategy to protect against insulin resistance and diabetes.