The controlled termination of signaling pathways after their ligand-induced activation is an important mechanism to ensure appropriate signal intensity and the consequent cellular response. Most cell surface receptors are downregulated by receptor endocytosis and subsequent lysosomal degradation, processes accompanied by attachment of ubiquitin (Ub) molecules to activated receptors and associated proteins. A significant body of evidence supports the view that mono-Ub functions as an important internalization and degradation signal conserved from yeast to mammals. Yet, the mechanisms underlying ligand-dependent receptor endocytosis seem to be divergent and more complex in mammalian cells. This is not only a consequence of evolution-based expansion of endocytic proteins and protein-interaction domains, but is also caused by enhanced formation of networks and multi-molecular complexes linked to activated receptors in higher eukaryotes. Here, we discuss the current view on the role of Ub-dependent and -independent pathways in receptor internalization and endocytosis in mammalian cells.