Given the central role c-Myc plays in growth control, differentiation and apoptosis, understanding how c-Myc functions will increase our understanding about normal cell development, and how alterations in these processes can lead to malignancy. C-Myc is a negative regulator of terminal myeloid differentiation; therefore, it was of interest to determine what effect blocking c-Myc expression would have on proliferation and differentiation. In this work we showed that blocking expression of either c-Myc or Max, its molecular partner, in myeloblastic leukemia M1 cells activated the differentiation program in the absence of an exogenous source of differentiation inducer; the cells assumed an intermediate stage myeloid morphology. Moreover, when both c-Myc and Max expression was concommitantly blocked, many of the cells underwent terminal differentiation. Finally, extending these studies to myeloblast enriched normal bone marrow (BM) cell has shown that blocking expression of either c-Myc or Max accelerated GM-CSF-induced differentiation along both the granulocytic and monocytic lineages. Thus, it can be concluded that blocking either c-Myc or Max expression in myeloid cells at specific stages of development activates and accelerates the terminal differentiation program.