DiscussionLigand-induced receptor dimerization is an early functional step in receptor activation, representing the most proximal, functional read-out for receptor activation. It is well understood that the family of Interleukin receptors will dimerize with the other members of its family leading to a complicated signaling cascade that is critically involved in a variety of auto-immune, inflammatory and oncogenic diseas-es. Surprisingly, existing cellular assays have been unable to faithfully monitor these interactions in a proximal manner to the receptor. Here we present a novel application of the Enzyme Fragment Complementation system to monitor receptor-receptor interactions at the surface of intact live cells, applicable to diverse receptor types such as Interleukin receptors, BMP receptors, receptor tyrosine kinases and cytokine receptors, with a specific focus on the interleukin family of receptors. The high specificity, simplicity of the assay protocol, large signal to noise ratio, serum tolerance and reproducibility of these assays has enabled their use in cell-based screening, functional characterization, QC lot release assays and neutralizing antibody studies. Examples discussed here include assays for the IL-1, IL-2, IL- 6, IL-10 receptor families, with assays developed or in development for ~85% of the Interleukins and their receptors.