To extravasate the bloodstream at specific targets, circulating immune cells must activate their integrins to undergo rapid in situ modulation of affinity or avidity for their endothelial ligands. This activation involves specialized sub-second G-protein signal transduction triggered by endothelium-displayed chemoattractants – primarily chemokines – and their cognate leukocyte-expressed G-protein-coupled receptors (GPCRs). Recently, we reported a rare autosomal-recessive leukocyte adhesion deficiency (LAD) syndrome associated with a defective ability of integrins to undergo GPCR-mediated stimulation at endothelial contacts. This LAD shows significant similarities to a group of integrin-activation syndromes reported in leukocytes and platelets. Here, the mechanisms by which GPCRs might regulate leukocyte and platelet integrins are outlined with respect to this new family of LAD cases. We propose to term this the LAD-III family.