The capacity for self-renewal is associated with progenitor cell populations and is lost upon differentiation. Aziz et al. discovered an exception to this rule when mouse monocytes and macrophages deficient in the transcription factors MafB and c-Maf were cultured in the presence of the growth factor, macrophage colony-stimulating factor (M-CSF). Under these conditions, MafB/c-Maf–deficient cells were able to divide continuously while maintaining the phenotype and function of mature cells. Unexpectedly, when these in vitro–cultured cells were transferred into mice, they did not induce tumors, despite continuing to divide, but rather incorporated themselves into tissues and adopted normal macrophage functions. Suppression of two genes involved in the self-renewal capacity of inducible pluripotent stem cells, KLF4 and c-Myc, inhibited the ability of MafB/c-Maf–deficient macrophages to self-renew. Such long-term propagation of a differentiated cell population that does not result in transformation when reintroduced in vivo has exciting therapeutic potential.