PI3K activation is the starting point of signaling pathways relaying on changes in the phosphorylation levels of membrane phosphoinositides. These pathways have been involved in several neuronal processes, including cellular growth and survival, differentiation, neuroprotection, dendritic growing, and synaptic plasticity among others. Recent data from Drosophila and rodents have demonstrated an unexpected role of PI3K controlling synapse number that lead to functional and behavioral effects. In the short-term, PI3K is also required for maintaining AMPA receptor clustering at the postsynaptic membranes. We review here the PI3K roles regulating synapse number and functionality.