Ligand-induced activation of transmembrane receptors activates intracellular signaling cascades that control vital cellular processes, such as cell proliferation, differentiation, migration and survival. Receptor signaling is modulated by several mechanisms to ensure that the correct biological outcome is achieved. One such mechanism, which negatively regulates receptor signaling, involves the modification of receptors with ubiquitin. This post-translational modification can promote receptor endocytosis and targets receptors for lysosomal degradation, thereby ensuring termination of receptor signaling. In this Commentary, we review the roles of ubiquitylation in receptor endocytosis and degradative endosomal sorting by drawing on the epidermal growth factor receptor (EGFR) as a well-studied example. Furthermore, we elaborate on the molecular basis of ubiquitin recognition along the endocytic pathway through compartment-specific ubiquitin-binding proteins and highlight how endocytic sorting machineries control these processes. In addition, we discuss the importance of ubiquitin-dependent receptor endocytosis for the maintenance of cellular homeostasis and in the prevention of diseases such as cancer.