Apolipoprotein E (apoE) is a widely expressed multifunctional protein. Much of the attention in the literature on this apolipoprotein is devoted to its role in cardiovascular disease and Alzheimer’s disease. While hepatocytes are the major site of apoE expression, numerous non-hepatic cells and tissues also express apoE. The viability of mice with global deficiency of apoE suggests that it is not essential for embryogenesis and development. Nonetheless, the widespread expression of apoE in these non-hepatic cells suggests that it may have an important impact on physiology and metabolism outside of its role in lipoprotein and cellular lipid homeostasis and Abeta clearance. In this review we discuss what is currently known about the role of apoE in various tissues including adipose, kidney, steroidogenic, and gonadal and central nervous system as well as its impact on immune cells and response to infections. Further investigation is needed to fully understand the impact of apoE expression in these tissues on development.