Axons that are physically separated from their cell soma undergo degradation through a process termed “Wallerian degeneration” (WD). This process, typically induced by acute injury, was initially thought to occur as a result of axons passively “wasting away” since they are no longer receiving nutrient supply from the soma. However, subsequent discoveries revealed that axons degenerate by activation of a prodegenerative signalling pathway and that inhibition of key elements of this pathway can protect axons. Furthermore, inhibiting WD in various disease models such as glaucoma, Parkinson’s disease and motor neuron disease protects axons from degeneration. One key element of WD is an intra-axonal calcium rise that occurs just before axons begin to fragment. Preventing this calcium rise delays the onset of axon fragmentation. To date, the full complement of ion channels responsible for this calcium influx have not been identified. Furthermore, the mechanism by which these calcium channels are activated is unknown. WD can be modeled in vitro by transecting axons of dorsal root ganglia (DRG), which separates them from their soma. We have used this model along with the Ca²⁺ sensor dye Fluo-4-AM to show that Ca²⁺ influx is reduced in axons treated with capsazepine (CPZ), an antagonist of the transient receptor potential cation channel vanilloid 1 (TRPV1), as well as in Trpv1-/- axons. Furthermore, CPZ-treated sensory neurons and DRGs of a Trpv1-/- background were partially rescued from degeneration after transection, indicating a prodegenerative role for TRPV1. We found that reactive oxygen species (ROS) mediate the activation of TRPV1 in this setting and, consistent with this, ROS-scavengers abolished Ca²⁺ influx in transected axons. Furthermore, we found that mitochondrial depolarization, a phenomenon that is known to occur during WD, triggers a ROS-dependent calcium influx through TRPV1 when initiated by the mitochondrial poison carbonyl cyanide m-chlorophenyl hydrazine (CCCP). CCCP also induces degeneration in cultured sensory neurons but is protected by Ca²⁺ chelation, ROS scavenging and inhibition of TRPV1 with CPZ. This thesis shows for the first time that TRPV1 is involved in WD and suggests that mitochondrial ROS are responsible for initiating calcium rise by sensitization of calcium channels.