Chemokines are small basic proteins defined by the number and position of the invariant cysteines in their protein sequence, with more than 40 identified that cluster into two major (CC and CXC) and two minor (CX3C and C) classes. They are potent chemoattractants and play an important role in host defense by mobilizing immune cells to combat invading microorganisms. In autoimmune diseases, where the immune system destroys its own cells, chemokines participate, making them important targets for treatment. Chemokines initiate immune cell activation by binding to cell surface receptors of the G protein-coupled receptor (GPCR) superfamily, with 19 functional chemokine receptors and two non-functional decoy receptors cloned. Around 50 million Americans, especially women, suffer from autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, asthma, creating a huge market for therapeutic approaches that could exceed $77 billion by 2017. Major pharmaceutical companies have invested heavily in research and development of chemokine receptor antagonists (a 2012 PubMed search with the term "chemokine receptor antagonists" lists over 4500 hits). Despite numerous chemokine receptor antagonists progressing from discovery into the clinic (Table 1), so far only two, the CCR5 inhibitor from Pfizer and the CXCR4 antagonist from Anormed, are registered drugs; these successes and failures are discussed further below.