Alterations in circulating lipids and ectopic lipid deposition impact on the risk of developing cardiovascular and metabolic diseases. Lipoprotein lipase (LPL) hydrolyzes fatty acids (FAs) from triglyceride (TAG)-rich lipoproteins including very low density lipoproteins (VLDLs) and chylomicrons, and regulates their distribution to peripheral tissues. Angiopoietin-like 4 (ANGPTL4) mediates the inhibition of LPL activity under different circumstances. Accumulating evidence associates ANGPTL4 directly with the risk of atherosclerosis and type 2 diabetes (T2D). This review focuses on recent findings on the role of ANGPTL4 in metabolic and cardiovascular diseases. We highlight human and murine studies that explore ANGPTL4 functions in different tissues and how these effect disease development through possible autocrine and paracrine forms of regulation.