The mysterious syndrome has sparked debate between veteran's groups, congressional investigators, and the military over questions of accountability, treatment, and compensation. Hypothesized causes have included parasites, biological and chemical warfare agents, prophylactic vaccines and medications given against biological and chemical warfare agents, fumes from oil well fires, and stress. In 1994 an advisory panel organized by the National Institutes of Health reported that the syndrome represented many illnesses and many causes; they deemed biological and chemical warfare agents unlikely as causes. Causes for the illnesses in many subsets of patients have been identified, e.g., some 30 veterans had leishmaniasis, a parasitic disease spread by sand flies, but in many instances the cause has not been identified.

In 1999 researchers said that brain scans of some sick veterans revealed signs of damage caused by exposure to toxic chemicals, and a study in 2004 suggested that some veterans may have been sensitive enough to otherwise low levels of poison gases to cause symptons associated with the syndrome. A committee appointed by Congress said in 2008 that evidence suggested that acetyl cholinesterase inhibitors, which include the nerve gas sarin, an anti-nerve-gas agent, and pesticides used against sand flies, and a genetic sensitivity to such chemicals may be the cause of the syndrome. Some medical historians have pointed out that syndromes of undiagnosable diseases have occurred after other wars, including World Wars I and II and the American Civil War.