The cell body of a lesioned neuron must receive accurate and timely information on the site and extent of axonal damage, in order to mount an appropriate response. Specific mechanisms must therefore exist to transmit such information along the length of the axon from the lesion site to the cell body. Three distinct types of signals have been postulated to underlie this process, starting with injury-induced discharge of axon potentials, and continuing with two distinct types of retrogradely transported macromolecular signals. The latter includes, on the one hand, an interruption of the normal supply of retrogradely transported trophic factors from the target, and, on the other hand, activated proteins originating from the injury site. This chapter reviews the progress on understanding the different mechanistic aspects of the axonal response to injury, and how the information is conveyed from the injury site to the cell body to initiate regeneration.