This review provides an overview of the established roles of CXCL8 signaling in CRC and subsequently discusses the possible strategies for targeting CXCL8 signaling in CRC drug resistance and progression, including indirect strategies (e.g., anti-inflammatory medications and NF-κB inhibitors) and direct strategies, such as CXCL8 inhibition or inhibition of its receptors (e.g., neutralizing antibodies, small-molecule receptor antagonists, and siRNAs) (see Table 1). Here, CXCL8 is linked to colorectal carcinoma.