In all transmembrane receptor systems the kinetics of receptor trafficking upon ligand stimulation is maintained in a balance between degradative and recycling pathways in order to keep homeostasis and to strictly control receptor-mediated signaling. Endocytosis is commonly considered as an efficient mechanism of uptake and transport of membrane-associated signaling molecules leading to attenuation of ligand-induced responses. Accumulating evidence, however, shows that signaling from internalized receptors not only continues in endosomal compartments, but that there are also distinct signaling events that require endocytosis. Endocytic organelles form a dynamic network of subcellular compartments, which actively control the timing, amplitude, and specificity of signaling. In this review we provide examples in which signal transduction either requires an active endocytic machinery, or directly originates from various types of endosomes. Based on recent discoveries, we emphasize the close interdependence between signaling and endocytosis, and the physiological relevance of endocytic transport in health and disease.