CXCR3 is a CXC chemokine receptor that, together with its three major ligands, CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC), is involved in inflammatory responses, mediated mainly by T cells. In several immune-related diseases, including chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), rheumatoid arthritis, multiple sclerosis, and atherosclerosis, CXCR3 and/or its ligands are found to be overexpressed, potentially indicating a role for this receptor in these diseases. Animal models have confirmed the therapeutic potential of targeting CXCR3 in the treatment of such diseases. Several peptidic, peptidomimetic, and small non-peptidomimetic CXCR3 ligands have been disclosed in the past 10 years. These ligands have served as chemical tools for the investigation of CXCR3 activation, blocking, and signaling, and some of these ligand series have been developed as potential therapeutic agents against inflammation. Computational modeling studies, facilitated by the recent developments in GPCR structural biology, together with mutagenesis and pharmacological studies, have aided in understanding how these ligands interact with CXCR3. This chapter will give an overview on how the combination of these chemical, computational, and pharmacological tools and techniques has increased our understanding of the molecular mechanisms by which small-molecule antagonists and agonists bind to CXCR3 compared to the relatively large chemokines. A detailed overview of CXCR3 ligand structure-activity relationships and structure-function relationships will be presented. This comparative analysis reveals that the full spectrum of antagonist and agonist effects on CXCR3 is now within reach by appropriate scaffolds and chemical modifications. Many of these ligands display behavior deviating from simple competition and do not interact with the chemokine binding site, providing evidence for an allosteric mode of action. Moreover, the computer-assisted molecular modeling of CXCR3 receptor-ligand interactions is discussed in view of GPCR crystal structures and mutagenesis studies of CXCR3 and other chemokine receptors. Improved insights in the interplay between CXCR3-ligand interactions and CXCR3-mediated signaling pathways potentially open up novel therapeutic opportunities in the area of inflammation.