Receptor-ligand interactions in blood flow are crucial to initiate such biological processes as inflammatory cascade, platelet thrombosis, as well as tumor metastasis. To mediate cell adhesion, the interacting receptors and ligands must be anchored onto two apposing surfaces of two cells or a cell and a substratum, i.e., two-dimensional (2D) binding, which is different from the binding of a soluble ligand in fluid phase to a receptor, i.e., three-dimensional (3D) binding. While numerous works have been focused on 3D kinetics of receptor-ligand interactions in the immune system, 2D kinetics and its regulations have been less understood, since no theoretical framework or experimental assays were established until 1993. Not only does the molecular structure dominate 2D binding kinetics, but the shear force in blood flow also regulates cell adhesion mediated by interacting receptors and ligands. Here, we provide an overview of current progress in 2D binding and regulations, mainly from our group. Relevant issues of theoretical frameworks, experimental measurements, kinetic rates and binding affinities, and force regulations are discussed. A neutrophil undergoes capture and rolling (or tethering) on the endothelium through selectin-PSGL-1 bonds, followed by slow rolling and firm adhesion through the -integrins LFA-1 and Mac-1 as well as intraluminal crawling and transmigration through the endothelium to the inflamed tissue.