Ubiquitylation is a posttranslational modification of proteins that is necessary for a variety of cellular processes. E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme, and E3 ubiquitin ligase are all involved in transferring ubiquitin to the target substrate to regulate cellular function. The objective of this review is to provide an overview of different aspects of E3 ubiquitin ligases that can lead to major biological system failure in several deadly diseases. The first part of this review covers the important characteristics of E3 ubiquitin ligases and their classification based on structural domains. Further, the authors provide some online resources that help researchers explore the data relevant to the enzyme. The following section delves into the involvement of E3 ubiquitin ligases in various diseases and biological processes, including different types of cancer and neurological disorders.