Antihistamines and decongestants often are used interchangeably and in combination for a variety of upper respiratory illnesses ranging from allergic rhinitis to the common cold; yet, these two classes of drugs have distinct therapeutic actions. When administered alone, antihistamines are of no value in reducing nasal stuffiness. Therefore, many allergy products also contain decongestants. Conversely, cough-cold remedies often contain antihistamines despite their lack of efficacy in these conditions. Nasal congestion, on the other hand, regardless of its cause, responds quite well to decongestants. The topical route provides a faster and more intense decrease in nasal airway resistance, but has a shorter duration and the potential to produce rebound congestion in patients with allergic rhinitis, whereas oral agents do not. Phenylpropanolamine, pseudoephedrine, and phenylephrine are the most common decongestants. Although all are sympathomimetic amines, their efficacy varies. In particular, phenylephrine is subject to first-pass metabolism and therefore is not bioavailable in currently recommended doses. In addition, phenylpropanolamine and pseudoephedrine, but not phenylephrine, are effective decongestants. Slow-release formulations allow a longer dosing interval, especially during the night. However, most formulations available in the United States are manufactured and sold without Food and Drug Administration scrutiny. Since the in vitro dissolution of many of these products differs, it is possible that some of the generic formulations are not bioequivalent to established brand-name products. Therefore, pharmacists should not substitute formulations without discussing the matter with the prescriber.