Spinal muscular atrophy (SMA) is a neuromuscular disease caused by abnormally low cellular levels of the ubiquitous protein SMN. Traditionally, reduced levels of SMN were thought to cause the selective death of lower motor neurons, leading to denervation and atrophy of skeletal muscles. However, numerous recent studies challenge the notion that SMA is solely a disease of lower motor neurons, indicating that SMA may actually be a multi-system disorder. There are several promising therapies for SMA, but effectively targeting treatment to all affected cells and tissues remains a major issue. Identifying and characterizing pathological changes that occur across all cell types and tissues affected by SMA is crucial for successfully developing new SMA therapeutics, and in this review we summarize recent developments in understanding the function of SMN in cells above and beyond motor neurons.