Signalling pathways that are activated by ligands binding to cell surface receptors are responsible for determining many aspects of cellular function and fate. Although this outcome is primarily determined by the nature of the ligand and its receptor, it is also essential that the array of intracellular enzymes, adaptor proteins and transcription factors are correctly assembled to convey the intended response. In recent years it has become apparent that proteins which regulate the amplitude and duration of these responses can also affect cell function and fate. The Cbl family of E3 ubiquitin ligases and adaptor proteins have now emerged as key negative regulators of signals from many surface receptors. Although the array of these receptors is diverse, they have a common link in that they either possess a tyrosine kinase domain or they form associations with cytoplasmic protein tyrosine kinases (PTKs). Thus Cbl proteins become involved in signaling responses at a time when PTKs are first activated and therefore provide an initial line of defense to ensure signaling responses proceed at the desired intensity and kinetics.