Contrary to a century-old belief that dendritic spines are stable storage sites of long term memory, the emerging picture from a recent flurry of exciting observations using novel high resolution imaging methods of living cells in culture is that of a dynamic structure, which undergoes fast morphological changes over periods of hours and even minutes. Concurrently, the nature of stimuli which cause formation or collapse of dendritic spines has changed from a mysterious Hebbian-governed plasticity producing stimulus to the more trivial activation of the synapse by strong/weak stimulation. The molecular mechanisms underlying spine plasticity are beginning to emerge; the role of presynaptic and/or postsynaptic activity, genetic, central or local factors in the formation and retraction of spines are currently being analyzed. A common mechanism for both, formation/elongation and pruning/retraction of spines, involving changes in intracellular calcium concentration ([Ca(2+)](i)), is emerging. It appears that [Ca(2+)](i) is related to changes in spines in a bell shape form: lack of synaptic activity causes transient outgrowth of filopodia but eventual elimination of spines, a moderate rise in [Ca(2+)](i) causes elongation of existing spines and formation of new ones, while a massive increase in [Ca(2+)](i) such as that seen in seizure activity, causes fast shrinkage and eventual collapse of spines. Nuclear signals (e.g. CREB), activated by an increase in [Ca(2+)](i), are involved in the central regulation of spine formation, while spine shrinkage and elongation are probably triggered by local [Ca(2+)](i) changes. This hypothesis provides a parsimonious explanation for conflicting reports on activity-dependent changes in dendritic spine morphology. Still, the many differences between cultured neurons, with which most of current studies are conducted, and the neuron in the real brain, require a cautious extrapolation of current assumptions on the regulation of spine formation.