This article reviews the published clinical experience of the use of the third-generation cephalosporins in the treatment of rare infections. Rare infections are defined as those caused by unusual pathogens or multi-resistant organisms as well as those occurring in unusual or pharmacologically protected body sites. Examples of such infections are uncommon causes of meningitis and ventriculitis, brain abscess, rare causes of bacterial endocarditis, metastatic Salmonella infections, spontaneous bacterial peritonitis and liver abscess, late complications of Lyme borreliosis, uncommon Pseudomonas infections, and post-reconstructive surgery Aeromonas cellulitis. Although these data are largely anecdotal, they form a useful body of information, providing guidance on the management of similar problems encountered by other doctors, while suggesting areas of further investigation for the management of a variety of unusual infections with the third-generation cephalosporins.