Dendritic spines are the principal recipients of excitatory synaptic inputs and the basic units of neural computation in the mammalian brain. Alterations in the density, size, shape, and turnover of mature spines, or defects in how spines are generated and establish synapses during brain development, could all result in neuronal dysfunction and lead to cognitive and/or behavioral impairments. That spines are abnormal in fragile X syndrome (FXS) and in the best-studied animal model of this disorder, the Fmr1 knockout mouse, is an undeniable fact. But the trouble with spines in FXS is that the exact nature of their defect is still controversial. Here, we argue that the most consistent abnormality of spines in FXS may be a subtle defect in activity-dependent spine plasticity and maturation. We also propose some future directions for research into spine plasticity in FXS at the cellular and ultrastructural levels that could help solve a two-decade-long riddle about the integrity of synapses in this prototypical neurodevelopmental disorder.