Neisseria gonorrhoeae and Neisseria meningitidis are human-specific pathogens and the etiologic agents for the sexually transmitted infection gonorrhea and bacterial meningitis, respectively. Several closely related, human-restricted, commensal Neisseria spp. share an anatomical niche with N. meningitidis. These commensal Neisseria spp. rarely cause pathology since they are not seen as foreign and do not trigger the innate immune system. In this chapter, we discuss how the pathogenic Neisseria spp. may have evolved from a single commensal progenitor by gaining the ability to elicit inflammation. This ancestor then evolved into the present-day pathogens through the acquisition of several additional factors and mechanisms of interacting with host cells, tissues, and molecules and the possibility that the pathogenic ancestor may have also given rise to several commensal species. To help elucidate these evolutionary steps, we will define core colonization determinants shared between the commensal and pathogenic organisms and then, in contrast, define determinants and properties shared by or unique to each pathogenic species. Of note, the pathogenic Neisseria spp. possess a complex set of diversity generation systems, indicating an advantage of such systems in the pathogenic Neisseria spp. lifestyle, and we will focus on the pilin antigenic variation system, which provides some of the best clues about the evolutionary relationship between the species. These analyses will lead to our model for how some organisms that damage their host (e.g., organisms we call pathogens) can arise from organisms that do not damage their host and could also evolve to lose pathogenicity.