An expanded polyglutamine (polyQ) tract at the amino-terminus of the androgen receptor (AR) confers toxic properties responsible for neuronal and non-neuronal degeneration in spinal and bulbar muscular atrophy (SBMA), one of nine polyQ expansion diseases. Both lower motor neurons and peripheral tissues, including skeletal muscle, are affected, supporting the notion that SBMA is not a pure motor neuron disease but a degenerative disorder of the neuromuscular system. Here, we review experimental evidence demonstrating both nerve and muscle degeneration in SBMA model systems and patients. We propose that polyQ AR toxicity targets these components in a time-dependent fashion, with muscle pathology predominating early and motor neuron loss becoming more significant at late stages. This model of pathogenesis has important therapeutic implications, suggesting that symptoms arising from degeneration of nerve or muscle predominate at different points and that directed interventions targeting these components will be variably effective depending upon disease progression.