Diacetyl is the simplest diketone. It occurs endogenously in humans, is a natural byproduct of bacterial fermentation and pyrolysis of organic matter, and is present naturally in a number of foods. In its pure form, diacetyl is a greenish‐yellow liquid that is moderately soluble in water and has a very strong buttery, quinone‐like, or chlorine‐like odor. It has been used as a synthetic food additive and flavoring, most notably in microwave popcorn, for its buttery and caramel or toffee notes; however, since the mid‐2000s, its use has declined in favor of substitutes. Diacetyl has also been used as a reactant or starting material in chemical and/or biochemical reactions. Exposure to the general population is ubiquitous, not just from use and consumption of flavored consumer products and foods, but also through naturally occurring diacetyl in various foodstuffs and beverages and direct or secondhand exposure to tobacco smoke. Diacetyl has low toxicity from ingestion and dermal exposure. Its respiratory toxicity potential has been thoroughly evaluated via animal studies. As with most volatile organic compounds, the most sensitive health endpoint is upper airways effects and inflammation. Findings from some epidemiological studies have suggested that, at very high concentrations, diacetyl may cause reduced lung function and even severe restrictive or obstructive lung diseases, including bronchiolitis obliterans. In addition, the weight of the evidence indicates that diacetyl is neither a teratogen, nor a carcinogen. Diacetyl's potential as a sensory irritant and respiratory sensitizer remains equivocal.