Neurotrophic factors, including the members of the neurotrophin family, play important roles in the development and maintenance of the nervous system. Trophic factor signals must be transmitted over long distances from axons and dendrites to the cell bodies of neurons. A mode of signaling well suited to the challenge of robust long distance signaling is the signaling endosome. We review the biology of signaling endosomes and the “signaling endosome hypothesis”. Evidence for disruption of signaling endosome function in disorders of the nervous system is also reviewed. Changes in endosome structure in Alzheimer disease (AD) and Down syndrome (DS) are present early in these disorders. Data for the APP products responsible are reviewed and the consequent changes in signaling from endosomes discussed. We conclude by pointing to the need for additional studies to explore the biology of signaling endosomes in normal neurons and to elucidate their role in the pathogenesis of neurodegeneration.