Significance The survival benefit of antiangiogenic therapies for cancer patients has been limited, potentially due to intrinsic/acquired resistance. Deciphering and targeting resistance mechanisms are critical to improving treatment outcome, especially in cancers where antiangiogenic therapies are standard of care, such as colorectal cancer (CRC). Consistent with our clinical findings, we found up-regulation of CXCL12/CXCR4 in orthotopic CRC models and conditional Apc mutant spontaneous rectal tumors after anti-VEGFR2 treatment. CXCR4 signaling recruited immunosuppressive innate immune cells such as Ly6C ^low monocytes and Ly6G ⁺ neutrophils to the CRCs, conferring resistance to VEGFR2 blockade. Furthermore, we successfully targeted these pathways genetically and pharmacologically, including with an FDA-approved agent Plerixafor (AMD3100), which significantly enhanced treatment response. These strategies have the potential for rapid clinical translation.