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Formoterol, a long-acting β2-receptor agonist, is used to relieve bronchial constriction. However, formoterol is often a racemic formulation, and contains both (R,R)- and (S,S)-enantiomers. Because the activity of each isomer is poorly defined, the mechanisms by which formoterol relaxes smooth muscle cells (SMCs) of intrapulmonary airways are not well understood. Consequently, we compared the effects of (S,S)-, (R,R)-, and racemic formoterol, as well as (R)-albuterol, on the contraction and Ca2+ signaling of airway SMCs in mouse lung slices with phase-contrast and confocal microscopy. Small airways were contracted with methacholine and the associated SMCs displayed sustained Ca2+ oscillations and an increase in Ca2+ sensitivity. These contracted airways displayed a substantial, concentration-dependent relaxation in response to (R,R)-formoterol. Racemic formoterol had a similar potency as (R,R)-formoterol for relaxing airways. By contrast, (S,S)-formoterol only induced a small relaxation. In conjunction with relaxation, (R,R)- and racemic formoterol stopped and decreased the methacholine-induced Ca2+ oscillations and Ca2+ sensitivity of the SMCs, respectively, whereas (S,S)-formoterol only decreased the Ca2+ sensitivity. In these studies, (R,R)- and racemic formoterol had a similar, but much greater, potency than (R)-albuterol for relaxing mice airways. This action was quickly initiated at high concentrations by decreasing the frequency of Ca2+ oscillations, but was more usually mediated at lower concentrations by decreasing the Ca2+ sensitivity of the SMCs.