It is well established that developmental maturity is a key factor regulating the response of lower motor neurons to injury. The influence of age on the survival of motor neuron cell somata following axotomy is well documented, but it remains unclear whether maturity also influences the degeneration of axonal and synaptic compartments at the neuromuscular junction. Such information is important for our interpretation of data suggesting that neonatal neuromuscular junctions are particularly vulnerable in neurodegenerative conditions that affect the developing postnatal nervous system, such as spinal muscular atrophy. Here, we have examined the role of development in regulating the vulnerability of mouse neuromuscular junctions to two mechanistically distinct degenerative insults: hypoxia and peripheral nerve injury. We report that neuromuscular junctions in neonatal mice are significantly more resistant to both hypoxia and nerve injury than those in adult mice, with a transition from the neonatal to adult phenotype occurring at 2-3 wk of age. We also demonstrate that the reduced vulnerability of neuromuscular junctions observed in neonatal mice is not determined by the maturity of the synapse per se, suggesting that properties associated with the neonatal environment and/or age of the neuron are responsible for modulating vulnerability. Our results are in stark contrast to previous studies showing that motor neuron cell somata are markedly more vulnerable to axotomy in neonatal mice. We conclude that neonatal neuromuscular junctions are resistant to a range of neurodegenerative insults in vivo and that this resistance is developmentally regulated.