As a multifunctional cytokine, tumor necrosis factor alpha (TNF-alpha) exerts a series of biological actions in different cells, tissues, organs, and species and has been demonstrated to regulate and interfere with energy metabolism, especially lipid homeostasis. A large body of researches suggested that the effects of TNF-alpha on lipid metabolism mainly include five aspects: (1) suppresses free fatty acid (FFA) uptake and promotes lipogenesis; (2) induces lipolysis; (3) inhibits lipid-metabolism-related enzymes activity; (4) regulates cholesterol metabolism; (5) regulates other adipocyte-derived adipokines. The molecular mechanisms underlying these actions are complex and several signal transduction pathways might be involved. Regulation of metabolism-related gene expression at transcriptional and protein levels and impact on enzymes activity might be of importance. Identification and verification of these pathways might provide novel potential strategies and drug targets for dyslipidemia therapy. However, the inconsistent and even conflict conclusions on lipid profile drawn from human subjects after infliximab therapy poses the possibility that the effect of TNF-alpha on lipid metabolism might be more complicated than it appeared to be.