Evasion of apoptotic cell death is critical for tumorigenesis and it is widely believed that expression of anti-apoptotic Bcl-2 family members at endogenous levels is essential to sustain survival of cells undergoing neoplastic transformation. Previous studies using gene-targeted mice have shown that Bcl-xL, but surprisingly not Bcl-2 is critical for Myc-induced pre-B/B lymphoma development. It remains, however, unclear whether Bcl-xL is the sole pro-survival Bcl-2 family member required for tumorigenesis induced by deregulated Myc expression. Mcl-1, another Bcl-2 pro-survival family member, is critical for cell survival during the early stages of B lymphopoiesis and is expressed at abnormally high levels in several types of human B cell lymphomas where it causes resistance to chemotherapeutic drugs. We therefore examined the role of Mcl-1 in pre-B/B lymphoma development in Eµ-myc transgenic mice, a model of human Burkitt’s lymphoma, in which Myc over-expression under control of the immunoglobulin heavy chain gene enhancer (Eµ) causes abnormally increased accumulation of pre-leukaemic pro-B/pre-B cells, which after acquisition of additional oncogenic mutations progresses to a malignant state. Remarkably, our results show that loss of only one allele of mcl-1 is sufficient to diminish the pre-leukaemic expansion of B lymphoid cells and to substantially prolong lymphoma-free survival of Eµ-myc transgenic mice. We therefore conclude that Mcl-1 is a key player, alongside with Bcl-xL, in Eµ-myc driven B cell lymphoma development.