Pseudomonas fluorescens is not generally considered a bacterial pathogen in humans; however, multiple culture-based and culture-independent studies have identified it at low levels in the indigenous microbiota of various body sites. With recent advances in comparative genomics, many isolates originally identified as the “species” P. fluorescens are now being reclassified as novel Pseudomonas species within the P. fluorescens “species complex.” Although most widely studied for its role in the soil and the rhizosphere, P. fluorescens possesses a number of functional traits that provide it with the capability to grow and thrive in mammalian hosts. While significantly less virulent than P. aeruginosa, P. fluorescens can cause bacteremia in humans, with most reported cases being attributable either to transfusion of contaminated blood products or to use of contaminated equipment associated with intravenous infusions. Although not suspected of being an etiologic agent of pulmonary disease, there are a number of reports identifying it in respiratory samples. There is also an intriguing association between P. fluorescens and human disease, in that approximately 50% of Crohn's disease patients develop serum antibodies to P. fluorescens. Altogether, these reports are beginning to highlight a far more common, intriguing, and potentially complex association between humans and P. fluorescens during health and disease.