Because of recent efforts performed to create new medications for the treatment of elevated triglyceride blood levels, there is increasing interest in deeply understanding the lipoprotein lipase enzyme structure and mechanism of action. The purpose of this article is to summarize the recent studies of molecular structure and regulation of lipoprotein lipase enzyme (LPL), describing the correlation of this enzyme with the pathogenesis of cardiovascular diseases. Highlights in this article: • X-ray crystallography of Lipoprotein lipase enzyme (LPL) revealed that the enzyme is not only active in a homodimer complex with GPIHBP1, but also in the monomeric form. • Recent genetic association studies and annotation data-base suggested that tissue LPL is not only recognized as TG hydrolyzing key enzyme but also a modulator in many cellular mechanisms, including regulation of cell response to several macronutrients, mediating cellular events associated to immune cell response, controlling the proliferation of hematopoietic stem cells as well as regulation of cell response to insulin hormone.