Adhesion of biological cells is mediated by the specific binding of receptors and ligands which are typically large proteins spanning through the plasma membranes of the contacting cells. The receptors and ligands can exhibit affinity for nanoscale lipid clusters that form within the plasma membrane. A central question is how these nanoscale lipid clusters physically affect and respond to the receptor–ligand binding during cell adhesion. Within the framework of classical statistical mechanics we find that the receptor–ligand binding reduces the threshold energy for lipid clusters to coalesce into mesoscale domains by up to ∼50%, and that the formation of these domains induces significant cooperativity of the receptor–ligand binding. The interplay between the receptor–ligand binding cooperativity and the lipid domain formation manifests acute sensitivity of the membrane system to changes in control parameters. This sensitivity can be crucial in cell signaling and immune responses.