The activation of signalling pathways by ligand engagement with transmembrane receptors is responsible for determining many aspects of cellular function and fate. While these outcomes are initially determined by the nature of the ligand and its receptor, it is also essential that intracellular enzymes, adaptor proteins and transcription factors are correctly assembled to convey the intended response. In recent years, it has become evident that proteins that regulate the amplitude and duration of these signalling responses are also critical in determining the function and fate of cells. Of these, the Cbl family of E3 ubiquitin ligases and adaptor proteins has emerged as key negative regulators of signals from many types of cell-surface receptors. The array of receptors and downstream signalling proteins that are regulated by Cbl proteins is diverse; however, in most cases, the receptors have a common link in that they either possess a tyrosine kinase domain or they form associations with cytoplasmic PTKs (protein tyrosine kinases). Thus Cbl proteins become involved in signalling responses at a time when PTKs are first activated and therefore provide an initial line of defence to ensure that signalling responses proceed at the desired intensity and duration.