A number of studies in the past 20 years have shown that perturbation of activity of the nervous system leads to compensatory changes in synaptic strength that serve to return network activity to its original level. This response has been termed homeostatic synaptic plasticity. Despite the intense interest in homeostatic synaptic plasticity, little attention has been paid to its role in the prototypic synaptic disease, myasthenia gravis. In this review, we discuss mechanisms that have been shown to mediate homeostatic synaptic plasticity at the mammalian neuromuscular junction. A subset of these mechanisms have been shown to occur in myasthenia gravis. The homeostatic changes occurring inmyasthenia gravis appear to involve the presynaptic nerve terminal andmay even involve changes in the excitability of motor neurons within the spinal cord. The finding of presynaptic homeostatic synaptic plasticity in myasthenia gravis leads us to propose that changes in the motor unit in myasthenia gravis may be more widespread than previously appreciated.