Chemokine receptors have a key role in the pathogenesis of autoimmune diseases, inflammation and viral infection. However, with the exception of selective CCR5 antagonists for HIV, the promise of obtaining new therapeutics related to chemokine receptors has not yet been realized. This article highlights some of the recent failures in the clinical trials of chemokine receptor antagonists and explores possible reasons as to why this might have occurred. Such reasons include the lack of predictability of animal models and redundancy of the target. A potential solution could be to develop drugs that target more than one receptor--known as polypharmacology--which could be a novel way to generate effective therapeutics.