As the "human microbiome era" continues, there is an increasing awareness of our resident microbiota and its indispensable role in our fitness as holobionts. However, the host-microbe relationship is not so clearly defined for some human symbionts. Here we discuss examples of "accidental pathogens," meaning previously nonpathogenic and/or environmental microbes thought to have inadvertently experienced an evolutionary shift toward pathogenicity. For instance, symbionts such as Helicobacter pylori and JC polyomavirus have been shown to have accompanied humans since prehistoric times and are still abundant in extant populations as part of the microbiome. And yet, the relationship between a subgroup of these microbes and their human hosts seems to have changed with time, and they have recently gained notoriety as gastrointestinal and neuropathogens, respectively. On the other hand, environmental microbes such as Legionella spp. have recently experienced a shift in host range and are now a major problem in industrialized countries as a result of artificial ecosystems. Other variables involved in this accidental phenomenon could be the apparent change or reduction in the diversity of human-associated microbiota because of modern medicine and lifestyles. All of this could result in an increased prevalence of accidental pathogens in the form of emerging pathogens.