Over the past decade, several features of the B-cell receptor (BCR) complex have emerged as major markers for prognostic classification of B-cell chronic lymphocytic leukemia (B-CLL). In particular, the absence of somatic mutations within the immunoglobulin variable heavy chain genes (IGHV), the presence of ZAP-70 and a higher ability of the BCR to translate signals within the cell have been associated with an aggressive clinical course. Indeed, the stratification of patients with B-CLL based on BCR features suggests that heterogeneity of B-CLL clinical courses may reflect BCR signaling differences that have arisen during the evolution of leukemia. Therefore, characterizing BCR signaling profiles may help to identify signaling markers useful for patient stratification, disease monitoring and therapeutic targeting in B-CLL.