Neisseria gonorrhoeae is the cause of the sexually transmitted infection termed gonorrhoea, which afflicts over 100 million people worldwide each year. Since the mid-1940s, beginning with the availability of penicillin (Pen), antibiotic therapy has been the mainstay for curing infection and halting the spread of the gonococcus in the community. Unfortunately, gonococci developed resistance to Pen and many other antibiotics that were brought into clinical practice to counter act the growing problem of Pen (and other antibiotics) resistance. With the recent emergence of strains expressing resistance to the third-generation cephalosporins (cefixime and ceftriaxone) or other important antibiotics (macrolides and fluoroquinolones) there is considerable fear that without new antibiotics, gonorrhoea will become more difficult to treat; indeed, some have warned of the possibility of untreatable infections. In order to address this public health crisis of antibiotic resistant gonococci, it is essential that new bacterial targets are identified so as to facilitate the development of novel therapeutic drugs. I will discuss the role of the MtrC-MtrD-MtrE efflux pump in the development of gonococcal resistance to antibiotics and host-derived antimicrobials (e.g., cationic antimicrobial peptides). These phenotypes are augmented in gonococcal strains that have mutations that result in enhanced transcription of the mtrCDE efflux pump gene complex. I will provide evidence that this efflux pump is critical for the ability of gonococci to resist certain antibiotics as well as surviving during infection. Against this background, I will propose that this pump offers new targets for drug development (efflux pump inhibitors) and vaccine development to combat antibiotic resistant gonococcal strains and to prevent infections.