Various water-borne bacteria can cause significant illness. Illness most often results from ingestion of contaminated water or seafood, with gastrointestinal entry of pathogens or their byproducts. The skin and soft tissues are also common entry points, either through trauma in or near the water, or by seawater contamination of an existing wound or break in the skin. Clinically significant water-borne illnesses are still rare. However, because humans are increasingly exposed to contaminated water sources through recreation or habitat, the rate of water-borne illnesses can be expected to increase. In patients who present with gastrointestinal illness or infections that do not respond to conventional therapy, water-borne pathogens should be considered in the differential diagnosis. A complete history, with attention to seafood ingestion and exposure to marine or freshwater life-forms, in conjunction with a high index of suspicion (especially in immunocompromised patients), will increase diagnostic accuracy in patients with water-borne illnesses.