The integrin family of adhesion receptors are involved in cell growth, migration and tumour metastasis. Integrins are heterodimeric proteins composed of an alpha and a beta subunit, each with a large extracellular, a single transmembrane, and a short cytoplasmic domain. The dynamic regulation of integrin affinity for ligands in response to cellular signals is central to integrin function. This process is energy dependent and is mediated through integrin cytoplasmic domains. However, the cellular machinery regulating integrin affinity remains poorly understood. Here we describe a genetic strategy to disentangle integrin signalling pathways. Dominant suppression occurs when overexpression of isolated integrin beta1 cytoplasmic domains blocks integrin activation. Proteins involved in integrin signalling were identified by their capacity to complement dominant suppression in an expression cloning scheme. CD98, an early T-cell activation antigen that associates with functional integrins, was found to regulate integrin activation. Furthermore, antibody-mediated crosslinking of CD98 stimulated beta1 integrin-dependent cell adhesion. These data indicate that CD98 is involved in regulating integrin affinity, and validate an unbiased genetic approach to analysing integrin signalling pathways.