Abstract : About 35 years after the first in vitro studies of the insulin receptor, considerable progress has been accomplished in the structural biology of the insulin-receptor interaction, and of the receptor tyrosine kinase family in general. This brief review attempts to assemble the various pieces of the puzzle, despite the lack of a detailed crystallographic structure of the insulin-receptor complex, and to establish a model that explains the mechanism of receptor activation, its negative cooperativity, and the triggering of intracellular signalling pathways