THE protein IRS-1 acts as an interface between signalling proteins with Src-homology-2 domains (SH2 proteins) and the receptors for insulin, IGF-1, growth hormone, several interleukins (IL-4, IL-9, IL-13) and other cytokines(1-7). It regulates gene expression acid stimulates mitogenesis, and appears to mediate insulin/IGF-1-stimulated glucose transport(8). Thus, survival of the IRS-1(-/-) mouse with only mild resistance to insulin was surprising(9,10). This dilemma is provisionally resolved with our discovery of a second IRS-signalling protein, We purified and cloned a likely candidate called 4PS from myeloid progenitor cells and, because of its resemblance to IRS-1, we designate it IRS-2. Alignment of the sequences of IRS-2 acid IRS-1 revealed a highly conserved amino terminus containing a pleckstrin-homology domain and a phosphotyrosine-binding domain, and a poorly conserved carboxy terminus containing several tyrosine phosphorylation motifs. IRS-2 is expressed in many cells, including tissues from IRS-1(-/-) mice(11), and may be essential for signalling by several receptor systems.