Single molecule atomic force microscopy was used to characterize structure, binding strength (unbinding force), and binding kinetics of a classical cadherin, vascular endothelial (VE)-cadherin, secreted by transfected Chinese hamster ovary cells as cis-dimerized full-length external domain fused to Fc-portion of human IgG. In physiological buffer, the external domain of VE-cadherin dimers is a ≈20-nm-long rod-shaped molecule that collapses and dissociates into monomers (V-shaped structures) in the absence of Ca²⁺. Trans-interaction of dimers is a low-affinity reaction (K_D = 10⁻³–10⁻⁵ M, k_off = 1.8 s⁻¹, k_on = 10³–10⁵ M⁻¹·s⁻¹) with relatively low unbinding force (35–55 pN at retrace velocities of 200–4,000 nm·s⁻¹). Higher order unbinding forces, that increase with interaction time, indicate association of cadherins into complexes with cumulative binding strength. These observations favor a model by which the inherently weak unit binding strength and affinity of cadherin trans-interaction requires clustering and cytoskeletal immobilization for amplification. Binding is regulated by low-affinity Ca²⁺ binding sites (K_D = 1.15 mM) with high cooperativity (Hill coefficient of 5.04). Local changes of free extracellular Ca²⁺ in the narrow intercellular space may be of physiological importance to facilitate rapid remodeling of intercellular adhesion and communication.