Synaptotagmin (Syt) proteins comprise a 17-member family of exocytosis regulators, several of which serve as Ca2+-sensing triggers for SNARE-catalyzed membrane fusion. Ca2+ dependence arises from two C-terminal C2 domains (termed C2A and C2B) that insert into anionic lipid membranes upon binding two or three Ca2+ ions. Of the Ca2+-sensitive isoforms, Syt-7 has recently emerged as a topic of broad interest due to its extreme Ca2+ sensitivity and roles in a diverse range of secretion events. Both C2 domains of Syt-7 (but especially C2A) bind and insert into membranes at much lower Ca2+ concentrations and dissociate more slowly than the corresponding domains from the more widely studied isoform Syt-1. We have used a combination of spectroscopic, single-molecule, and computational approaches to understand the physical-chemical origins of this strong membrane binding. The results show intriguing distinctions between Syt-1 and Syt-7, including deeper hydrophobic membrane insertion and more efficient membrane bridging by the Syt-7 C2A domain as well as diminished interdomain cooperativity in the Syt-7 C2AB tandem. Similarities between Syt-1 and Syt-7 inform models for a common mechanism of Syt/SNARE/Ca2+-mediated membrane fusion. Differences may contribute to the known points of divergence between the two isoforms, such as the rate of fusion pore expansion.