Interleukin (IL)-8 is the first discovered chemotactic cytokine, and its expression is up-regulated in a variety of solid tumors such as colorectal cancer, breast cancer, melanoma, and ovarian cancer. Recent studies have shown that the IL-8-CXCR1/2 axis can promote the infiltration of immunosuppressive cells, such as myeloid-derived suppressor cells, into the tumor microenvironment, angiogenesis, epithelial-mesenchymal transition, and the acquisition of stem-like phenotypes by activating JAK/STAT, PI3K/Akt, and other signaling pathways. These signaling pathways can further promote tumor growth, invasion, metastasis, and drug resistance. Recently, IL-8 is considered to be a key factor in the regulation of the tumor microenvironment. More and more preclinical data suggest that blockade of the IL-8-CXCR1/2 axis can enhance the tumor killing function of T cells and NK cells. The combining of inhibition of the IL-8-CXCR1/2 axis with immune checkpoint inhibitors may be a promising treatment strategy for tumor. Here, we review the role of the IL-8-CXCR1/2 signaling pathway in tumor occurrence, development, metastasis, and immunosuppression, and the research and clinical trials of drugs targeting the IL-8-CXCR1/2 signaling pathway.