The sulfonamide group is widely used in medicinal chemistry and appears in many marketed drugs in a variety of forms. One class of drugs that contain this group has been termed the 'sulfonamide antibacterials'. These compounds are inhibitors of tetrahydropteroic acid synthetase. Sulfonamide antibacterials are derivatives of 4-aminobenzenesulfonamide, in which the sulfonamide moiety acts as an isostere of the carboxylic acid group of the natural substrate 4-aminobenzoic acid. The 4-amino group is essential for activity in this class of compounds. These drugs, however, can cause hypersensitivity and severe skin rash, toxicities which are now associated with the presence of the aniline structure (4-amino), although, historically, the class affect was referred to as 'sulfa allergy'. This class effect has also been wrongly associated with other sulfonamide-containing drugs in a number of cases, and has led to warnings and labels that are not scientifically correct. This review explains how this confusion arose and illustrates the scientific evidence indicating that the sulfonamide group is an essential and safe part of the medicinal chemist's arsenal.