The clustering of platelet glycoprotein receptors with cytosolic YxxL and YxxM motifs, including GPVI, CLEC-2 and PEAR1, triggers activation via phosphorylation of the conserved tyrosine residues and recruitment of the tandem SH2 (Src homology 2) domain effector proteins, Syk and PI 3-kinase. We have modelled the clustering of these receptors with monovalent, divalent and tetravalent soluble ligands and with transmembrane ligands based on the law of mass action using ordinary differential equations and agent-based modelling. The models were experimentally evaluated in platelets and transfected cell lines using monovalent and multivalent ligands, including novel nanobody-based divalent and tetravalent ligands, by fluorescence correlation spectroscopy. Ligand valency, receptor number, receptor dimerisation, receptor phosphorylation and a cytosolic tandem SH2 domain protein act in synergy to drive receptor clustering. Threshold concentrations of a CLEC-2-blocking antibody and Syk inhibitor act in synergy to block platelet aggregation. This offers a strategy for countering the effect of avidity of multivalent ligands and in limiting off-target effects. Author summary: All cells in the body have proteins in the membrane known as receptors which have the ability to recognise a wide variety of extracellular stimuli. This interaction generates signals into the cell which control cell behaviour. In this study, we have used two different computational methods to predict how the binding of stimuli leads to the clustering of a subset of receptors which is required to generate the signals. We have then tested the models using advanced microscopy methods and by the generation of novel stimuli. Our results show that clustering of receptors on the cell surface can be achieved through at least 3 mechanisms that work together to generate large clusters which induce powerful signals. Over 70% of drugs target receptors on the cell surface. However, many have side-effects that can limit their use in patients. We show that simultaneously targeting 2 of the mechanisms reduces the concentration of drug needed for inhibition thus reducing the side-effects. [ABSTRACT FROM AUTHOR]