Free‐living amebae of the genera Acanthamoeba , Balamuthia , Naegleria , and Sappinia are rare causes of infectious diseases in humans with the exception of Acanthamoeba keratitis (AK), which is reported in over 10,000 soft contact lens wearers annually worldwide. Unlike several Acanthamoeba species, which can cause both AK and granulomatous amebic encephalitis (GAE), only one species of Naegleria , Naegleria fowleri , is known to infect humans by causing an acute, fulminant, usually lethal, central nervous system (CNS) infection, known as primary amebic meningoencephalitis (PAM). 1–6 Both Acanthamoeba species and N fowleri are distributed worldwide; found commonly in freshwater; and have even been isolated from tap water, air conditioning systems, and improperly maintained swimming pools. 1–5 Balamuthia mandrillaris , formerly known as leptomyxid ameba, is another opportunistic, free‐living ameba. Like Acanthamoeba spp, B mandrillaris is capable of causing skin lesions and GAE in individuals with compromised or competent immune systems, who inhale infective spores or develop indolent, granulomatous skin lesions in soil‐contaminated wounds. Lastly, Sappinia pedata , a recently identified free‐living ameba that lives in soil and domestic animal feces, has caused a single case of non‐GAE in an immunocompetent Texas farmer. CNS infections caused by these ubiquitous organisms remain rare despite expanding world populations; but are, nevertheless, increasing today due to a combination of factors including increased freshwater recreational activities during heat waves for PAM, more immunocompromised individuals susceptible to GAE, and more soft contact lens wearers at risk of AK. 6,7 The purpose of this review will be to describe the epidemiology, pathophysiology, clinical manifestations, diagnosis, and management of free‐living amebic infections. In addition, United States Centers for Disease Control and Prevention (CDC) laboratory‐confirmed cases of PAM, B mandrillaris GAE, and AK will be analyzed statistically to determine significant risk factors for exposure and infection; and to … Corresponding Author: James H. Diaz, MD, MPH&TM, Dr PH, School of Public Health, Louisiana State University Health Sciences Center (LSUHSC) in New Orleans, 1615 Poydras Street, Suite 1400, New Orleans, LA 70112, USA. E‐mail: jdiaz{at}lsuhsc.edu