Starting with multipotent progenitors, hematopoietic lineages are specified by lineage-restricted transcription factors. The transcription factors that determine the decision between lymphoid and myeloid cell fates, and the underlying mechanisms, remain largely unknown. Here, we report that enforced expression of C/EBPalpha and C/EBPbeta in differentiated B cells leads to their rapid and efficient reprogramming into macrophages. C/EBPs induce these changes by inhibiting the B cell commitment transcription factor Pax5, leading to the downregulation of its target CD19, and synergizing with endogenous PU.1, an ETS family factor, leading to the upregulation of its target Mac-1 and other myeloid markers. The two processes can be uncoupled, since, in PU.1-deficient pre-B cells, C/EBPs induce CD19 downregulation but not Mac-1 activation. Our observations indicate that C/EBPalpha and beta remodel the transcription network of B cells into that of macrophages through a series of parallel and sequential changes that require endogenous PU.1.