SYNAPTOTAGMINS (Syts) are brain-specific Ca²⁺/phospholipidbinding proteins^1–5. In hippocampal synapses, Syt I is essential for fast Ca²⁺-dependent synaptic vesicle exocytosis but not for Ca^{2 +}- independent exocytosis³. In vertebrates and invertebrates^6–9, Syt may therefore participate in Ca2^{2 +}–dependent synaptic membrane fusion, either by serving as the Ca^{2 +} sensor in the last step of fast Ca^{2 +}-triggered neurotransmitter release, or by collaborating with an additional Ca^{2 +} sensor. While Syt I binds Ca^{2 +}(refs 10,11), its phospholipid binding is triggered at lower calcium concentrations (EC₅₀ = 3–6µM) than those required for exocytosis12. Furthermore, Syts bind clathrin–AP2 with high affinity, indicating that they may play a general role in endocytosis^4,5 rather than being confined to a specialized function in regulated exocytosis³. Here we resolve this apparent contradiction by describing four Syts, three of which (Syt VI, VII and VIII) are widely expressed in non-neural tissues. All Syts tested share a common domain structure, with a cytoplasmic region composed of two C2 domains that interacts with clathrin–AP2 (K_d = 0.1–1.0nM) and with neural and non-neural syntaxins. The first C₂ domains of Syt I, II, III, V and VII, but not of IV, VI or VIII, bind phospholipids with a similar Ca²⁺–concentration dependence (EC₅₀ = 3–6µM). The same C₂ domains also bind syntaxin as a function of Ca^{2 +} but the Ca^{2 +}–concentration dependence of Syt I, II and V (>200 µM) differs from that of Syt III and VII (<10 µM). Syts therefore appear to be ubiquitous proteins with a role in exocytosis mediated by syntaxin binding. The Ca^{2 +}levels needed to trigger syntaxin binding by the different Syts suggest that they play distinct roles in membrane fusion; the level required by Syt I approximates those required for synaptic exocytosis.