Bronchodilators are the cornerstone of symptomatic treatment for all chronic obstructive pulmonary disease (COPD) severity stages when administered on a regular basis to prevent or reduce symptoms and exacerbations. The principal inhaled bronchodilator treatments are beta-2 agonists and anticholinergics, used singularly or in combination. There is good evidence that regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting bronchodilators. Long-acting agents include the twice-daily beta-2 agonists formoterol and salmeterol, the once-daily anticholinergic tiotropium, and, more recently, the once-daily beta-2 agonist indacaterol. Long-acting bronchodilators have been shown to improve multiple clinical outcomes in COPD in comparison to short-acting agents including lung function, symptoms, dyspnea, quality of life, and exacerbations. Studies of head-to-head comparisons of long-acting bronchodilators are scant but indicate superior bronchodilation of tiotropium over salmeterol, while preliminary data from trials with the novel once-daily beta-2 agonist indacaterol indicate superior bronchodilation and clinical efficacy over twice-daily long-acting beta-2 agonists and at least equipotent bronchodilation as once-daily tiotropium. These recent therapeutic developments in COPD represent a change of paradigm with a shift from short-acting bronchodilators with multiple dosing per day to reduced dosing frequency and prolonged duration of action including once-daily treatment. This review summarizes relevant data and landmark studies comparing the efficacy of short-acting versus longer-acting bronchodilators in COPD, including new data for once-daily indacaterol, and discusses potential mechanism underlying the improved efficacy of long-acting versus short-acting bronchodilators.