The stromal cell–derived factor 1 (SDF-1) chemokine has various effects on hematopoietic cell functions. Its role in migration and homing of hematopoietic progenitors is currently well established. Previously it was shown that SDF-1 stimulates myeloid progenitor proliferation in synergy with cytokines. Results of this study indicate that SDF-1 alone promotes survival of purified CD34⁺ cells from human unmobilized peripheral blood (PB) by counteracting apoptosis as demonstrated by its capacity to reduce DNA fragmentation, annexin-V⁺ cell number, and APO2.7 detection and to modulate bcl-2 homolog protein expression. The study demonstrates that SDF-1, produced by sorted CD34⁺CD38⁺ cells and over-released in response to cell damage, exerts an antiapoptotic effect on CD34⁺ cells through an autocrine/paracrine regulatory loop. SDF-1 participates in the autonomous survival of circulating CD34⁺ cells and its effect required activation of the phosphotidyl inositol 3 kinase (PI3-K)/Akt axis. Cell sorting based on Hoechst/pyroninY fluorescences shows that SDF-1 production is restricted to cycling CD34⁺ cells. SDF-1 triggers G₀ quiescent cells in G₁ phase and, in synergy with thrombopoietin or Steel factor, makes CD34⁺ cells progress through S+G₂/M phases of cell cycle. By assessing sorted CD34⁺CD38⁻ and CD34⁺CD38⁺ in semisolid culture, the study demonstrates that SDF-1 promotes survival of clonogenic progenitors. In conclusion, the results are the first to indicate a role for endogenous SDF-1 in primitive hematopoiesis regulation as a survival and cell cycle priming factor for circulating CD34⁺ cells. The proposal is made that SDF-1 may contribute to hematopoiesis homeostasis by participating in the autonomous survival and cycling of progenitors under physiologic conditions and by protecting them from cell aggression in stress situations.