The protein product of c-cbl proto-oncogene is known to interact with several proteins, including Grb2, Crk and PI3 kinase, and is thought to regulate signalling by many cell surface receptors. The precise function of c-Cbl in these pathways is not clear, although a genetic analysis in Caenorhabditis elegans suggests that c-Cbl is a negative regulator of the epidermal growth factor receptor. Here we describe a yeast two hybrid screen performed with c-Cbl in an attempt to further elucidate its role in signal transduction. The screen identified interactions involving c-Cbl and two 14-3-3 isoforms, cytokeratin 18, human unconventional myosin IC, and a recently identified SH3 domain containing protein, SH3 P17. We have used the yeast two hybrid assay to localise regions of c-Cbl required for its interaction with each of the proteins. Interaction with 14-3-3 is demonstrated in mammalian cell extracts.