PURPOSE: Radioresistance of cancer cells remains a fundamental barrier for 
maximum efficient radiotherapy. Tumor heterogeneity and the existence of 
distinct cell subpopulations exhibiting different genotypes and biological 
behaviors raise difficulties to eradicate all tumorigenic cells. Recent evidence 
indicates that a distinct population of tumor cells, called cancer stem cells 
(CSC), is involved in tumor initiation and recurrence and is a putative cause of 
tumor radioresistance. There is an urgent need to identify the intrinsic 
molecular mechanisms regulating the generation and maintenance of resistance to 
radiotherapy, especially within the CSC subset. The chemokine C-X-C motif 
receptor 4 (CXCR4) has been found to be a prognostic marker in various types of 
cancer, being involved in chemotaxis, stemness and drug resistance. The 
interaction of CXCR4 with its ligand, the chemokine C-X-C motif ligand 12 
(CXCL12), plays an important role in modulating the tumor microenvironment, 
angiogenesis and CSC niche. Moreover, the therapeutic inhibition of the 
CXCR4/CXCL12 signaling pathway is sensitizing the malignant cells to 
conventional anti-cancer therapy.
CONTENT: Within this review we are summarizing the role of the CXCR4/CXCL12 axis 
in the modulation of CSC properties, the regulation of the tumor 
microenvironment in response to irradiation, therapy resistance and tumor 
relapse.
CONCLUSION: In light of recent findings, the inhibition of the CXCR4/CXCL12 
signaling pathway is a promising therapeutic option to refine radiotherapy.