When nerve terminals in the brain are stimulated, a group of phosphoproteins called the dephosphins are coordinately dephosphorylated by calcineurin, the Ca(2+)-dependent protein phosphatase. Amazingly, the seven presently known dephosphins are not structurally related, yet each has been independently shown to be essential for synaptic vesicle endocytosis (SVE). Nowhere else in biology is there a similar example of the coordinated dephosphorylation of such a large group of proteins each sharing roles in the same biological response. This suggests that dephosphorylation and phosphorylation of the dephosphins is essential for SVE. Recent studies in synaptosomes have confirmed this view, with calcineurin-mediated dephosphorylation of the dephosphins essential for triggering SVE. The phosphorylation cycle of the dephosphins might regulate SVE by targeting the proteins to sites of action and by stimulating the assembly of several large essential endocytic protein complexes.