Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand (often the endogenous hormone or peptide) at the same receptor.[1] Functional selectivity can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor.[2] Functional selectivity, or biased signaling, is most extensively characterized at G protein coupled receptors (GPCRs).[3] A number of biased agonists, such as those at muscarinic M2 receptors tested as analgesics[4] or antiproliferative drugs,[5] or those at opioid receptors that mediate pain, show potential at various receptor families to increase beneficial properties while reducing side effects. For example, pre-clinical studies with G protein biased agonists at the μ-opioid receptor show equivalent efficacy for treating pain with reduced risk for addictive potential and respiratory depression.[1][6] Studies within the chemokine receptor system also suggest that GPCR biased agonism is physiologically relevant. For example, a beta-arrestin biased agonist of the chemokine receptor CXCR3 induced greater chemotaxis of T cells relative to a G protein biased agonist.[7]