The insulin receptor (IR) and Type 1 insulin-like growth factor receptor (IGF-1R) are homodimeric α2β2 glycoproteins that together, with the insulin-receptor related receptor, form the insulin receptor family of receptor tyrosine kinases. While both IR and IGF-1R possess high-affinities for their cognate ligands (insulin, and IGF-I and IGF-II, respectively), they can also bind and be activated by the reciprocal ligands. Activation of either receptor affects downstream PI3K- AKT and RAS-RAF-MAPK signalling, with varying effects on cellular glucose metabolism, differentiation and proliferation. Aberrant signalling leads to a number of clinical manifestations including diabetes (in the case of IR) and cancer (in the case of IGF-1R and possibly IR), making both receptors attractive pharmaceutical targets. The primary extracellular ligand binding site of either receptor is a tandem element comprising the first leucine-rich repeat domain (L1) of one receptor α-chain, in association with the C-terminal region (αCT) of the opposite receptor α-chain. Disruption of the L1 and αCT association disrupts ligand binding. 114,000 small-molecules within an in-house library were screened for their ability to disrupt this site within the IR/IGF-1R system. Identified hits were subsequently confirmed in an equivalent surface plasmon resonance assay. Further refinement of hit compounds will require X-ray crystallographic pharmacophore determination and the development of an assay measuring receptor activation kinetics, of which, recent progress has ben made.