The association between dietary fat intake and chronic disease has been researched for more than 60 years. Cardiovascular disease (CVD) continues to be a leading cause of global mortality, accounting for 17.3 million deaths in 2013, equivalent to 31.5% of total deaths. One out of every three deaths in the United States is attributed to heart disease, stroke, or other forms of CVD; an estimated average of one death every second and more than 330 billion dollars in health expenditures and lost productivity. Moreover, the incidence of obesity has doubled from 1980 to 2015 in more than 40 countries and is associated with chronic diseases such as cardiovascular (atherosclerosis) and type 2 diabetes. Selecting diets that provide energy from monounsaturated and polyunsaturated fats are also beneficial to consumer health. Fats and oils are the source of many nonesterified fatty acids that act as signaling molecules to regulate gene expression that controls body homeostasis, including lipid metabolism. This article describes how dietary fats and oils, and related derived products are involved in chemical and biochemical mechanisms that define the safety and toxicity of dietary lipid consumption.