The Haematopoietically-expressed homeobox gene, Hhex, is a transcription factor that is important for definitive haematopoiesis and B-cell development during embryogenesis12 . In addition, we and others have shown that Hhex is upregulated by multiple transcription factors in T-cell acute lymphoblastic leukaemia (T-ALL), where it may play a key role in mediating thymocyte self-renewal34 . To study the role of Hhex in adult haematopoietic development we have utilised an Hhex Inducible Knock-Out (iKO) mouse. Whilst targeted Hhex deletion using the Mx-Cre transgene caused no deleterious health effects, the mice showed a progressive loss of B lymphocytes in the circulation, spleen and bone marrow (BM). Moreover, within the BM a complete loss of B-cell progenitors was observed along with an accumulation Common Lymphocyte Progenitor cells (CLPs). An aberrant B-cell population (CD19+/B220-) was also observed in the circulation, spleen and BM of the Hhex iKO mice which within the BM expressed high levels of CD93 and c-Kit, suggesting these cells represent a developmentally blocked B-cell progenitor. To determine whether these effects were intrinsic to Hhex-null haematopoietic cells, transplantation experiments were performed. Strikingly, these showed an almost complete failure of Hhex-null haematopoietic stem cells to produce both T and B lymphocytes. Thus, Hhex is essential for T-lymphopoiesis in addition to its previously described role in B-lymphopoiesis. Analysis of Hhex-null multipotent progenitor cells showed multiple disregulated lymphoid genes. Hhex-null CLPs could not form B-cells in vitro, an effect that was restored by retroviral expression of Hhex. Collectively these results illustrate the fundamental importance of Hhex to lymphoid development and warrant further investigation into its role in the development and maintenance of lymphoid malignancies.