Antimicrobial peptides (AMPs) constitute a critical component of innate host defense during infections as they have both direct and indirect microbicidal action. However, successful pathogens have evolved multiple mechanisms to evade or otherwise resist AMPs. Both constitutive and inducible mechanisms of AMP-resistance likely enhance the ability of pathogens to survive and proliferate in vivo before adaptive immune responses become available. Using the sexually transmitted human pathogen Neisseria gonorrhoeae as an example, I will provide evidence that AMP-resistance systems promote bacterial fitness and survival during infection. Moreover, AMP-resistance systems possessed by N. gonorrhoeae are of clinical significance as they often function to decrease the efficacy of clinically useful antibiotics by virtue of changes in the cell envelope that influence permeability or efflux of antimicrobials. The underlying genetic and regulatory processes that control AMP-resistance as well as their importance during infection may provide insights for new therapeutic strategies that are needed during this time of concern about the emergence of antibiotic resistant pathogens and their associated diseases.