During a progression of acute renal failure (ARF), renal tubular S3-segment is sensitive to ischemic stresses. For reversing tubular damage, resident tubular cells proliferate, and bone marrow-derived cells (BMDC) can be engrafted into injured tubules. However, how resident epithelium or BMDC are involved in tubular repair remains unknown. Using a mouse model of ARF, we examined whether hepatocyte growth factor (HGF) regulates a balance of resident cell proliferation and BMDC recruitment. Within 48-hours post-renal ischemia, tubular destruction became evident, followed by 2-waved regenerative events: 1) tubular cell proliferation between 2 and 4 days, along with an increase in blood HGF; and 2) appearance of BMDC in the tubules from 6 days post-ischemia. When anti-HGF IgG was injected in the earlier stage, tubular cell proliferation was inhibited, leading to an increase of BMDC in renal tubules. Under the HGF-neutralized states, stromal cell-derived factor-1 (SDF1) levels increased in renal tubules, associated with the enhanced hypoxia. Administrations of anti-SDF1-receptor IgG into ARF mice reduced the number of BMDC in interstitium and tubules. Thus, possible cascades include: 1) inhibition of tubular cell proliferation by neutralizing HGF leads to renal hypoxia and SDF1 up-regulation; and 2) BMDC are eventually engrafted in tubules through SDF1-mediated chemotaxis. Inversely, administration of recombinant HGF suppressed the renal hypoxia, SDF1 up-regulation and BMDC engraftment in ARF mice by enhancing resident tubular cell proliferation. Thus, we conclude that HGF is a positive regulator for eliciting resident tubular cell proliferation, and SDF1 for BMDC engraftment during the repair process of ARF.