Third-generation cephalosporins play a pivotal role in the management of infections because of their potent and broad-spectrum antimicrobial activity, proven clinical efficacy in a wide variety of infections, safety, and potential for cost savings. Selection of third-generation cephalosporins poses a dilemma, however, particularly for clinicians who view the six antibiotics within this class as interchangeable. Choice of drug should be based on antimicrobial spectrum and other factors such as lack of resistance development and cost considerations. This review focuses on the distinguishing features of the parenteral third-generation cephalosporins. Such differences suggest the need for retiring the convenient "generation" classification system for cephalosporins in favor of a system that encourages recognition of clinically important features of each agent in this diverse group of cephalosporin antibiotics.