Gonorrhea is the second most commonly reported notifiable disease in the United States; 350,062 gonorrhea cases were reported in 2014. Sexually transmitted infections caused by Neisseria gonorrhoeae are a cause of pelvic inflammatory disease in women, which can lead to serious reproductive complications including tubal infertility, ectopic pregnancy, and chronic pelvic pain. Prevention of sequelae and of transmission to sexual partners relies largely on prompt detection and effective antimicrobial treatment. However, treatment has been compromised by the absence of routine antimicrobial susceptibility testing in clinical care and evolution of antimicrobial resistance to the antibiotics used to treat gonorrhea. 2014. The Gonococcal Isolate Surveillance Project (GISP) was established in 1986 as a sentinel surveillance system to monitor trends in antimicrobial susceptibilities of N. gonorrhoeae strains in the United States. Each month, N. gonorrhoeae isolates are collected from up to the first 25 men with gonococcal urethritis attending each of the participating sexually transmitted disease (STD) clinics at 27 sites. The number of participating sites has varied over time (21-30 per year). Selected demographic and clinical data are abstracted from medical records. Isolates are tested for antimicrobial susceptibility using agar dilution at one of five regional laboratories. A total of 5,093 isolates were collected in 2014. Of these, 25.3% were resistant to tetracycline, 19.2% to ciprofloxacin, and 16.2% to penicillin (plasmid-based, chromosomal, or both). Reduced azithromycin susceptibility (Azi-RS) (defined as minimum inhibitory concentration [MIC] ≥2.0 µg/mL) increased from 0.6% in 2013 to 2.5% in 2014. The increase occurred in all geographic regions, but was greatest in the Midwest, and among all categories of sex of sex partners (men who have sex with men [MSM], men who have sex with men and women [MSMW], and men who have sex with women [MSW]). No Azi-RS isolates exhibited reduced cefixime or ceftriaxone susceptibility (Cfx-RS and Cro-RS, respectively). The prevalence of Cfx-RS (MIC ≥0.25 µg/mL) increased from 0.1% in 2006 to 1.4% in both 2010 and 2011, decreased to 0.4% in 2013, and increased to 0.8% in 2014. Cro-RS (MIC ≥0.125 µg/mL) increased following a similar pattern but at lesser percentages (increased from 0.1% in 2008 to 0.4% in 2011 and decreased to 0.1% in 2013 and 2014). The percentage of isolates resistant to tetracycline, ciprofloxacin, penicillin, or all three antimicrobials, was greater in isolates from MSM than from MSW. This is the first report to present comprehensive surveillance data from GISP and summarize gonococcal susceptibility over time, as well as underscore the history and public health implications of emerging cephalosporin resistance. Antimicrobial susceptibility patterns vary by geographic region within the United States and by sex of sex partner. Because dual therapy with ceftriaxone plus azithromycin is the only recommended gonorrhea treatment, increases in azithromycin and cephalosporin MICs are cause for concern that resistance to these antimicrobial agents might be emerging. It is unclear whether increases in the percentage of isolates with Azi-RS mark the beginning of a trend. The percentage of isolates with elevated cefixime MICs increased during 2009-2010, then decreased during 2012-2013 after treatment recommendations were changed in 2010 to recommend dual therapy (with a cephalosporin and a second antibiotic) and a higher dosage of ceftriaxone. Subsequently, the treatment recommendations were changed again in 2012 to no longer recommend cefixime as part of first-line therapy (leaving ceftriaxone-based dual therapy as the only recommended therapy). Despite the MIC decrease (i.e., trend of improved cefixime susceptibility) during 2012-2013, the increase in the number of strains with Cfx-RS in 2014 underscores the potential threat of cephalosporin-resistant N. gonorrhoeae. The National Strategy for Combating Antibiotic-Resistant Bacteria identifies prevention, rapid detection, and control of outbreaks of ceftriaxone-resistant N. gonorrhoeae infection as a priority for U.S. Antimicrobial susceptibility surveillance is conducted to guide development of treatment recommendations for effective therapy and prevention of complications from and transmission of gonorrhea. Federal agencies can use GISP data to develop national treatment recommendations and set research and prevention priorities. Local and state health departments can use GISP data to determine allocation of STD prevention services and resources, guide prevention planning, and communicate best treatment practices to health care providers. Continued surveillance, appropriate treatment, development of new antibiotics, and prevention of transmission remain the best strategies to reduce gonorrhea incidence and morbidity.