The chemokine family is composed of small chemotactic cytokines and receptors that mediate the infiltration of various immune cells. According to the position of the cysteine residues in the amino terminal end, chemokines are divided into four subfamilies, while others classify chemokines according to their function to be either inflammatory, homeostatic, or both. On the other hand, chemokine receptors are G-protein-coupled receptors that activate various signaling pathways, while the atypical receptors act as decoy scavenger receptors. Chemokines play crucial roles in health and disease, especially in tumor biology. They could aid in the migration of immune cells toward the tumor that eventually change the tumor microenvironment (TME). Also, chemokines regulate and directly interact with cancerous cells as well as other cell types present in the TME. Dysregulation of chemokine expression in various cancer types highlighted their activities in cancer progression which may have a strong association with patients’ prognosis and response to therapy. Further, chemokines have an impact on cellular processes associated with tumor progression including proliferation, stemness, angiogenesis, invasion, and metastasis. Consequently, the chemokine family may present diagnostic and prognostic biomarker potential as well as being promising targets for immunotherapy. In this chapter, we highlight the direct effects of chemokines on neoplastic cells and cellular processes associated with cancer development and progression. Finally, the impact of current anti-cancer therapies on chemokine/chemokine receptor expression and the potential of current chemokine-targeted therapies are explored whether as monotherapy or combinatorial with chemotherapy and immunotherapy.