The development of resistance to multiple antibiotics has limited treatment options for gonorrhea in many countries. Currently, the Centers for Disease Control and Prevention only recommend cephalosporin antibiotics for treatment of uncomplicated gonorrhea. Although the cephalosporins remain effective, the demonstrated ability of Neisseria gonorrhoeae to develop resistance has raised concerns about the possibility of multidrug-resistant N. gonorrhoeae strains, which include cephalosporin resistance. This article provides a review of global trends in cephalosporin susceptibility among gonococcal isolates, recent findings that deepen our understanding of genetic mechanisms of resistance, and the public health and clinical implications of the potential emergence of cephalosporin-resistant gonorrhea.