Lipoprotein lipase (LPL) is essential for the hydrolysis and distribution of triglyceride-rich lipoprotein-associated fatty acids among extrahepatic tissues. Additionally, the enzyme facilitates several non-lipolysis associated functions including the cellular uptake of whole lipoprotein particles and lipophilic vitamins. The tissue-specific variations of LPL expression have been implicated in the pathogenesis of various lipid disorders, obesity and atherosclerosis. Transgenic technology provided the means to study the physiological response to the overexpression or absence of the enzyme in adipose tissue, muscle and macrophages. The effects of varying LPL expression in adipose tissue and muscle are summarized in this article.