Neurons of both the central and the peripheral nervous system are critically dependent on neurotrophic signals for their survival and differentiation. The trophic signal is originated at the axonal terminals that innervate the target(s). It has been well established that the signal must be retrogradely transported back to the cell body to exert its trophic effect. Among the many forms of transmitted signals, the signaling endosome serves as a primary means to ensure that the retrograde signal is delivered to the cell body with sufficient fidelity and specificity. Recent evidence suggests that disruption of axonal transport of neurotrophin signals may contribute to neurodegenerative diseases such as Alzheimer's disease and Down syndrome. However, the identity of the endocytic vesicular carrier(s), and the mechanisms involved in retrogradely transporting the signaling complexes remain a matter of debate. In this review, we summarize current insights that are mainly based on classical hypothesis-driven research, and we emphasize the urgent needs to carry out proteomics to resolve the controversies in the field.