Lipoprotein lipase, hepatic lipase, and endothelial lipase play a pivotal role in the clearance and remodelling of plasma lipoproteins. Their activity is governed at the level of gene transcription as well as via changes in enzyme activity by specific activator or inhibitor proteins. The latter group includes two members of the Angiopoietin family: Angiopoietin-like proteins 3 and 4 (Angptl3, Angptl4). Angptl4 is expressed ubiquitously and is a direct target gene of the peroxisome proliferator activated receptors, whereas Angptl3 is expressed exclusively in liver and is regulated by the liver X receptor. For both Angptl4 and Angptl3, injection of recombinant protein, adenoviral over-expression, and transgene-mediated overexpression have been shown to cause marked hypertriglyceridemia. Conversely, inactivation of the Angptl4 or Angptl3 gene is associated with lower plasma triglyceride levels. Recent human genetic studies suggest that rare or common sequence variants in the ANGPTL4 and ANGPTL3 gene, respectively, impact plasma TG levels, supporting a role for ANGPTL4 and ANGPTL3 in lipoprotein metabolism in humans. The present chapter provides an overview of the role of Angptl4 and Angptl3 in the regulation of lipoprotein metabolism. It is postulated that alterations in Angptl4 and Angptl3 signalling might be involved in dyslipidemia.