Spinal muscular atrophy is typically characterized as a motor neuron disease. Untreated patients with the most severe form, spinal muscular atrophy type 1, die early with infantile-onset progressive skeletal, bulbar, and respiratory muscle weakness. Such patients are now living longer due to new disease-modifying treatments such as gene replacement therapy (onasemnogene abeparvovec), recently approved by the US Food and Drug Administration, and nusinersen, a central nervous system-directed treatment which was approved by the US Food and Drug Administration three years ago. This has created an area of pressing clinical need: if spinal muscular atrophy is a multisystem disease, dysfunction of peripheral tissues and organs may become significant comorbidities as these patients survive into childhood and adulthood. In this review, we have compiled autopsy data, case reports, and cohort studies of peripheral tissue involvement in patients and animal models with spinal muscular atrophy. We have also evaluated preclinical studies addressing the question of whether peripheral expression of survival motor neuron is necessary and/or sufficient for motor neuron function and survival. Indeed, spinal muscular atrophy patient data suggest that spinal muscular atrophy is a multisystem disease with dysfunction in skeletal muscle, heart, kidney, liver, pancreas, spleen, bone, connective tissues, and immune systems. The peripheral requirement of SMN in each organ and how these contribute to motor neuron function and survival remains to be answered. A systemic (peripheral and central nervous system) approach to therapy during early development is most likely to effectively maximize positive clinical outcome.