High-density lipoprotein (HDL) and its main protein component apolipoprotein (apo)A-I, play an important role in cholesterol homeostasis. It has been demonstrated that HDLs comprise of a very heterogeneous group of particles, not only regarding size but also composition. HDL's best described function is its role in the reverse cholesterol transport, where lipid-free apoA-I or small HDLs can accept and take up cholesterol from peripheral cells and subsequently transport this to the liver for excretion. However, several other functions have also been described, like anti-oxidant, anti-inflammatory and anti-thrombotic effects. In this article, the general features, synthesis and metabolism of apoA-I and HDLs will be discussed. Additionally, an overview of HDL functions will be given, especially in the context of some major pathologies like cardiovascular disease, cancer and diabetes mellitus. Finally, the therapeutic potential of raising HDL will be discussed, focussing on the difficulties of the past and the promises of the future.