Endocytosis is essential for virtually all eukaryotic cells to internalize nutrients, antigens, pathogens, and cell surface receptors from the plasma membrane into membrane-bounded, endocytic vesicles to regulate cell homeostasis, cell signaling, and development. Distinct mechanisms mediate endocytic uptake of a large variety of distinctly sized cargoes ranging from small molecules to viruses or bacteria. Common to all of these endocytic pathways is the deformation of the plasma membrane by intracellular factors including scaffolding proteins, amphipathic peripheral membrane proteins, and lipid-modifying enzymes. In this review we summarize how different cargoes exploit distinct pathways for cell entry, and how proteins assist the generation of curved membrane domains during internalization.