The physiological roles of chemokine receptors have expanded beyond host defense and now represent important targets for intervention in several disease indications. Chemokine receptors have joined the ranks of other members of the G-protein-coupled receptor (GPCR) family in therapeutic potential as small-molecule chemokine receptor antagonists move from discovery to the clinic. Chemokine receptors belong to the rhodopsin family of GPCRs and, as such, are expected to be closely related in structure to other Class A members. In this review, we summarize information that is pertinent to chemokine receptors as therapeutic targets, the status of low molecular weight antagonists in clinical development, molecular modeling of receptor-small-molecule interactions, and the challenges that face drug discovery and development programs.