Far from being a simple attenuator, endocytosis is now also implicated in the initiation and propagation of signals. Signaling reciprocates by controlling endocytosis and contributing to its ability to selectively sort receptors. It appears that the quiet days of endocytosis as a relatively “stand-alone” process are over, as we expose the intricate network that connects it to actin, membrane dynamics, lipids metabolism, signaling adaptors, and transducers. Phenotypically, this is mirrored by an important role of endocytosis in proliferation, differentiation, cell survival, neurotransmission, embryogenesis, and cell fate specification. An emerging role of alterations of the endocytic machinery in diseases is therefore predicted.