<b><i>Background:</i></b> Chemokines are a family of proteins mainly mediating the homing and migration of various cells. The CXC chemokine CXCL12 is a member of low-weight-molecular chemokines. In the kidney, CXCL12 is pivotal for renal development and exerts a modulatory effect in kidney diseases under different etiologic settings by binding with CXC chemokine receptor 4 (CXCR4) or CXC chemokine receptor 7 (CXCR7). Besides, CXCL12 also exerts homeostasis influence in diverse physical conditions and various pathological situations. Thus, we conclude the complicated relationship between CXCL12 and kidney diseases in this review. <b><i>Summary:</i></b> In renal development, CXCL12 contributes a lot to nephrogenesis and the formation of renal vasculature via correlating with CXCR4. CXCL12 also plays an essential role in renal recovery from acute kidney injury. However, the CXCL12/CXCR4 axis plays a dual regulatory role in the initiation and development of diabetic kidney disease as well as chronic allogeneic nephropathy after kidney transplantation through dialectical consideration. Additionally, the CXCL12/CXCR4 link is considered as a new risk factor for lupus nephritis and renal cell carcinoma. <b><i>Key Messages:</i></b> Plenty of studies have presented the influence of CXCL12 and the relation with corresponding receptors in diverse biological and pathological statuses. Simultaneously, some drugs and antagonists targeting CXCL12/CXCR4 axis effectively treat various kidney diseases. However, more researches are needed to explore thorough influence and mechanisms, providing more cues for clinical treatments.

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