Non-alcoholic fatty liver disease (NAFLD), the major cause of abnormal liver function in the western world, is often associated with obesity and diabetes. In obese individuals, fat accumulation in the abdominal region affects both lipid and glucose metabolism, and a liver loaded with fat is insulin resistant. Insulin resistance (IR) is often associated with chronic low-grade inflammation, and numerous mediators released from immune cells and adipocytes contribute to development of IR. Recent results showing an important role for these mediators in NAFLD are providing us with a better understanding of this highly prevalent disease with implications for novel therapy development. This review highlights new aspects in development of liver steatosis and the relevance of various cytokines and adipocytokines in NAFLD.