Inhaled therapy remains the cornerstone of chronic obstructive pulmonary disease pharmacologic care, but some systemic treatments can be of help when the burden of the disease remains high. Azithromycin, phosphodiesterase-4 inhibitors, and mucoactive agents can be used in such situations. The major difficulty remains in the identification of the optimal target populations. Another difficulty is to determine how these treatments should be positioned in the global treatment algorithm. For instance, should they be prescribed in addition to other antiinflammatory agents or should they replace them in some cases? Research is ongoing to identify new therapeutic targets.