Neisseria gonorrhoeae is a major cause of pelvic inflammatory disease, ectopic pregnancy, and infertility, and it can facilitate human immunodeficiency virus (HIV) transmission. Emergence of gonococcal resistance to penicillin and tetracycline occurred during the 1970s and became widespread during the early 1980s. More recently, resistance to fluoroquinolones developed. Resistance was documented first in Asia, then emerged in the United States in Hawaii followed by other western states. It then became prevalent in all other regions of the United States. In Hawaii, fluoroquinolone resistance was first noted among heterosexuals; however, resistance in the United States initially became prevalent among men who have sex with men (MSM) before generalizing to heterosexuals. This emergence of resistance led CDC, in 2007, to discontinue recommending any fluoroquinolone regimens for the treatment of gonorrhea. CDC now recommends dual therapy for gonorrhea with a cephalosporin (ceftriaxone 250 mg) plus either azithromycin or doxycycline. This report summarizes trends in cephalosporin susceptibility among N. gonorrhoeae isolates in the United States during 2000-2010 using data from the Gonococcal Isolate Surveillance Project (GISP). During that period, the percentage of isolates with elevated minimum inhibitory concentrations (MICs) to cephalosporins (≥0.25 µg/mL for cefixime and ≥0.125 µg/mL for ceftriaxone) increased from 0.2% in 2000 to 1.4% in 2010 for cefixime and from 0.1% in 2000 to 0.3% in 2010 for ceftriaxone. Although cephalosporins remain an effective treatment for gonococcal infections, health-care providers should be vigilant for treatment failure and are requested to report its occurrence to state and local health departments. State and local public health departments should promote maintenance of laboratory capability to culture N. gonorrhoeae to allow testing of isolates for cephalosporin resistance. They also should develop enhanced surveillance and response protocols for gonorrhea treatment failures and report gonococcal treatment failures to CDC.