TNF-α was discovered more then 20 years ago as a cytokine implicated in a wide range of cell signaling pathways, many of which are known to lead to the activation of genes involved in inflammation and carcinogenesis. TNF-α is involved in the pathogenesis of many diseases, including Crohn's disease, diabetes, septic shock, tumorigenesis, rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. Multidisciplinary research endeavoring to understand the biomolecular and biomedicinal properties of TNF-α has never faded away, and the search for natural products able to inhibit TNF-α remains, to date, a hot topic of investigation. Over the last 10 years, many TNF-α-inhibiting natural compounds have been discovered, and their anti-TNF-α activities have been described. The present review describes the major cell signaling pathways activated by TNF-α and discusses the chemical and biological properties of TNF-α-inhibiting natural products, focusing on compounds that are able to inhibit TNF-α-related signal transduction pathways or TNF-α gene expression.