Genetic studies indicate that Cbl and Cbl-b, two highly homologous adaptor proteins, are involved in the negative regulation of thymocyte development and peripheral T-cell activation, respectively. The recent identification of Cbl proteins as RING-type E3 ubiquitin ligases might provide insights into their distinct immune regulatory functions, involving the targeting of different substrates for ubiquitination. The structural similarity and ubiquitous expression of Cbl and Cbl-b suggest, however, that they might also have overlapping functions in setting the thresholds for thymocyte selection and mature T-cell signaling.