Persistent activity-induced synaptic modification is generally regarded as the cellular basis for developmental refinement of neuronal connections and for learning and memory. It has long been recognized that synaptic modifications can be reversed by subsequent stimuli. Recent in vivo studies indicate that reversal of synaptic modifications is a natural process that can be triggered by physiological activity. Long-term potentiation (LTP) of hippocampal synapses in adult rats was reversed as rats entered a novel environment. LTP of retinotectal synapses in developing Xenopus was also reversed by subsequent spontaneous activity. Repetitive stimulation with spaced patterns, however, can overcome this reversal, leading to stabilized synaptic modifications. The requirement of spaced stimulus patterns for stable synaptic modifications could ensure appropriate refinement of developing connections.