Axonal transport ensures long-range delivery of essential components and signals between proximal and distal areas of the neuron, and it is crucial for neuronal homeostasis and survival. Several pathogens and virulence factors use this route to gain access to the central nervous system, exploiting the complex and still poorly understood trafficking mechanisms that regulate the dynamics of their cellular receptors. Studying the intracellular transport of neurotropic pathogens is therefore instrumental to glean new insights into these important molecular events. Botulinum (BoNT) and tetanus (TeNT) neurotoxins bind with high affinity to a variety of neurons and are internalised by specialised endocytic pathways leading to specific intracellular fates. Whereas BoNT trafficking is largely confined to the neuromuscular junction, TeNT is internalised in signalling endosomes shared with neurotrophins and their receptors, which are recruited to the fast axonal retrograde transport pathway. Recently, important paradigms regarding the mechanisms by which BoNT and TeNT interact with their cellular targets and are transported in neurons have been challenged. In this review, we summarise new findings concerning the uptake and intracellular trafficking of these neurotoxins, and discuss their implications in terms of the physiological effects of BoNT and TeNT in the central nervous system. © Springer-Verlag Berlin Heidelberg 2013.