The multifaceted roles of chemokines and of their receptors in physiological and pathological conditions have motivated researchers to analyze their involvement also in malignant diseases. This chapter focuses on CCL5 (RANTES) and its CCR5 receptor in cancer, describing their expression patterns, activities, and roles in several malignancies. Thus far, CCL5 and/or CCR5 have been detected in many hematological malignancies and in a large number of solid tumors; however, extensive studies on CCL5 and CCR5 were performed only in a limited number of cancers, including primarily multiple myeloma, breast cancer, and melanoma. This chapter discusses the major findings in these three specific malignancies, and addresses other cancers in which preliminary evidence was provided, including gastric cancer and ovarian cancer. In the framework of this chapter, we discuss the expression patterns of CCL5 and CCR5 in patients, their associations with disease course and experiments that were performed in animal model systems in order to decipher the roles of the CCL5/CCR5 axis in tumor growth and metastasis. In addition, we describe possible mechanisms mediating the activity of this pair in specific malignancies, and their effects on the tumor cells and on cells of the tumor microenvironment. Also, when it is of relevance, we consider the roles of other receptors for CCL5 (CCR1, CCR3) and of additional high-affinity chemotactic ligands for CCR5 (MIP-1α, CCL3; MIP-1β, CCL4). Taken together, the different studies suggest that even if the CCL5/CCR5 axis may have an anti-tumor potential under specific conditions, it turns into a detrimental entity in defined cancer diseases, such as multiple myeloma and breast cancer. Overall, CCL5/CCR5 may have major implications in cancer, and they should be considered as potential therapeutic targets for the limitation of specific malignant diseases.