Chemokines are the master regulators of leukocyte trafficking in inflammation. However, effectively targeting chemokines in inflammatory disease therapy requires agents that selectively block several chemokines. Ticks express salivary proteins (evasins) that inhibit chemokines, broadly suppressing host inflammation and supporting blood feeding. The structures of “Class A” evasins bound to chemokines, supported by mutational analyses, revealed the basis of their specificity for CC chemokines as well as features that control their selectivity amongst CC chemokines. These structural insights enabled rational engineering of evasins to tailor their chemokine selectivity. These studies provide a basis for development of evasins with applications in anti-inflammatory therapy.