An increasing number of proteins appear to perform multiple, sometimes unrelated functions in the cell. Such moonlighting properties have been recently demonstrated for proteins involved in clathrin-mediated endocytosis. Some clathrin adaptors and endosomal proteins can undergo nucleocytoplasmic shuttling, which is often based on intrinsic sequence motifs and requires active transport mechanisms. Endocytic proteins can associate with nuclear molecules, changing their localization and/or activity and may modulate the levels and specificity of gene transcription. It is not clear how the nuclear and cytoplasmic pools of endocytic proteins are interconnected, or whether these molecules act as nuclear second messengers upon extracellular stimuli, but alike in endocytosis, they seem to form multi-component scaffolding platforms in the nucleus. Added to their endocytic functions, the nuclear roles of Eps15, Epsin1, CALM, HIP1, Dab1/2, beta-arrestins, APPL1/2 and the components of ESCRTs clearly increase the complexity of signaling networks affecting cellular growth, proliferation and homeostasis.