Anticholinergics and beta-agonists reduce bronchoconstriction through different mechanisms, and there is a long history of combination therapy with short-acting agents in these classes for chronic obstructive pulmonary disease. Such combinations may allow lower doses and thereby improve safety. Oral theophylline has also been combined with short-acting bronchodilators for many years. Most studies, however, show only mild improvements in bronchodilation at the expense of increased adverse effects. Professional society guidelines recommend that as the symptoms of chronic obstructive pulmonary disease progress, the patient should receive regular treatment with one or more long-acting bronchodilators, and an inhaled corticosteroid if the patient has repeated exacerbations. The combination of a short-acting anticholinergic with a long-acting beta-agonist, or the combination of a long-acting anticholinergic with a short- or long-acting beta-agonist, has been shown in most studies to improve lung function versus monotherapy with the individual components. Systematic reviews have concluded that fluticasone and salmeterol, and budesonide and formoterol, are superior to placebo and lead to clinically meaningful improvements in lung function, exacerbation rate, and quality of life. Effects on survival are less clear. Some of the other issues to be resolved are the safety of combination therapy, its pharmacoeconomic impact, and the role of newer agents.