The prevention of and the controlling of symptoms, reductions in the frequency of exacerbations, and disease severity are central to the pharmacologic therapy of chronic obstructive pulmonary disease (COPD). COPD patients are inclined to be older, have more comorbidities, and use polypharmacy as a result. Long-acting inhaled muscarinic antagonists (LAMAs) is a preferred treatment modality. However, the cardiovascular (CV) safety of anti-cholinergics, including LAMA, has been an issue. In contrast, the results of the UPLIFT trial and a pooled analysis of data from 30 trials of tiotropium illustrates the association of tiotropium with reductions in the risk of all cause mortality, CV mortality and CV events. And, the UPLIFT trial provides clues regarding the additive advantages of tiotropium in COPD patients who already are using long-acting inhaled β2 agonists and inhaled corticosteroids. Following the contribution of tiotropium as a first LAMA, new LAMAs such as aclidinium and glycopyrrolate (NVA-237) seem to be emerging.