Although fiber is well recognized for its effect on laxation, increasing evidence supports the role of fiber in the prevention and treatment of chronic disease. The aim of this review is to provide an overview of the health benefits of fiber and its fermentation, and describe how the products of fermentation may influence disease risk and treatment. Higher fiber intakes are associated with decreased risk of cardiovascular disease, type 2 diabetes, and some forms of cancer. Fiber may also have a role in lowering blood pressure and in preventing obesity by limiting weight gain. Fiber is effective in managing blood glucose in type 2 diabetes, useful for weight loss, and may provide therapeutic adjunctive roles in kidney and liver disease. In addition, higher fiber diets are not contraindicated in inflammatory bowel disease or irritable bowel syndrome and may provide some benefit. Common to the associations with disease reduction is fermentation of fiber and its potential to modulate microbiota and its activities and inflammation, specifically the production of anti-inflammatory short chain fatty acids, primarily from saccharolytic fermentation, versus the deleterious products of proteolytic activity. Because fiber intake is inversely associated with all-cause mortality, mechanisms by which fiber may reduce chronic disease risk and provide therapeutic benefit to those with chronic disease need further elucidation and large, randomized controlled trials are needed to confirm causality. Teaching Points Strong evidence supports the association between higher fiber diets and reduced risk of cardiovascular disease, type 2 diabetes, and some forms of cancer. Higher fiber intakes are associated with lower body weight and body mass index, and some types of fiber may facilitate weight loss. Fiber is recommended as an adjunctive medical nutritional therapy for type 2 diabetes, chronic kidney disease, and certain liver diseases. Fermentation and the resulting shifts in microbiota composition and its activity may be a common means by which fiber impacts disease risk and management.