According to the World Health Organisation, 70% of all deaths globally can be attributed to chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, respiratory conditions, cardiovascular diseases, diabetes and cancer. Chronic inflammation has a significant impact on the quality of life of affected individuals with an increased risk of developing other chronic inflammatory diseases. Given the limitations of current pharmaceuticals, there is an intense research interest in identifying novel dietary interventions that can regulate and alleviate inflammation. A diet rich in cruciferous vegetables has been extensively studied for its immediate and long-term health benefits, particularly in the context of cardiovascular disease and cancer. Cruciferous vegetables contain the precursor glucoraphanin, which is hydrolysed upon consumption to form l-sulforaphane (LSF), the primary active compound that mediates potential cardio-protective and anti-carcinogenic effects. LSF has been shown to have beneficial effects in vitro and in animal studies through its classical antioxidant and anti-inflammatory properties, and more recently its chromatin modifying effects. This review discusses the clinical evidence to date in relation to the use of LSF in the context of chronic inflammatory diseases as well as provide key mechanistic insights for these effects.