In the developing nervous system, axons grow toward and innervate regions that can be as far away as the tip of the toe from the base of the spinal cord—as in the case of the sciatic nerve. To navigate through their surroundings and form functional synapses, axons need to respond to guidance signals in a spatiotemporally orchestrated manner. The growth cone at the tip of an axon provides a sensing compartment with specialized receptors that mediate the integration of all extracellular guidance cues. Many signaling pathways have been described to date, and for many, sole signaling from the cell surface does not describe the whole picture. Intracellular compartments called endosomes play a crucial role in the signaling of these receptors. They affect surface expression levels, form signaling hubs in which receptors can meet other receptors and co-receptors, and allow them to travel through the cell in a mechanism called intracellular trafficking. Routing receptors through specific endosomal compartments in a spatiotemporally defined fashion and in response to the cues presented to the axon helps in diversifying the signaling output. This explains how the restricted number of guidance cues and receptors can form a network of a myriad of different connections. At the same time, a complex system that relies on only a few components for a plethora of guidance decisions is prone to malfunctioning. In this chapter, we will summarize the signaling of axon guidance receptors and illustrate examples of human diseases related to errors in the axon guidance pathways.