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Bilirubin is the main waste product of heme catabolism. At high concentrations, bilirubin may cause toxicity, especially in the brain, kidney, and erythrocytes. Membrane and mitochondrial dysfunction, oxidative stress, apoptosis, necrosis, endoplasmic reticulum stress, excitotoxicity, inflammation, and epigenetic modifications are the main mechanisms of toxicity triggered by bilirubin in susceptible organs. Many studies have shown that there is an interaction between bilirubin and epigenetic modifications in metabolic and immune diseases. In this review, we first outline the toxicity mediated by bilirubin and then summarize the current knowledge linking bilirubin and epigenetic modifications in metabolic and immunometabolic disorders.