High-density lipoprotein (HDL) has been proposed to have several antiatherosclerotic properties, including the ability to mediate macrophage cholesterol efflux, antioxidant capacity, antiinflammatory properties, nitric oxide–promoting activity, and ability to transport proteins with their own intrinsic biological activities. 1 HDL particles are critical acceptors of cholesterol from lipid-laden macrophages and thereby participate in the maintenance of net cholesterol balance in the arterial wall and in the reduction of proinflammatory responses by arterial cholesterol-loaded macrophages. The pathways that regulate HDL-mediated macrophage cholesterol efflux and disposition of cholesterol involve cell membrane–bound transporters, plasma lipid acceptors, plasma proteins and enzymes, and hepatic cellular receptors (Figure 1). From the earliest proposed concept for HDL-mediated cholesterol efflux, 2, 3 the concentration of the cholesterol content in HDL particles has been considered a surrogate measurement for the efficiency of the “reverse cholesterol transport”(RCT) process; however, macrophagederived cholesterol represents a minor component of the cholesterol transported by HDL particles. 4–7 One important pathway for cholesterol-mediated efflux from macrophage foam cells involves interaction between the ATP-binding cassette transporter A1 (ABCA1) and cholesterol-deficient and phospholipid-depleted apolipoprotein (apo) AI complexes (pre-ß migrating HDL or very small HDL [HDL-VS]; Figure 2). 1, 8 Subsequently, the ATP-binding cassette transporter G1 (ABCG1) mediates macrophage cholesterol efflux through interactions (Figure 3) with spherical, cholesterolcontaining α-HDL particles (small HDL [HDL-S], medium HDL [HDL-M], large HDL [HDL-L], and very large (HDLVL). 1 In contrast, the scavenger receptor class B type I (SR-BI) is a multifunctional receptor that mediates bidirectional lipid transport in the macrophage, which is dependent on the content of cholesterol in lipid-laden macrophages. A more established role for SR-BI in cholesterol trafficking involves selective uptake of cholesteryl esters from mature HDL by the liver. Recent studies suggest that polymorphisms in SR-BI contribute to the functional capacity of this cholesterol disposition pathway, 9 thereby providing important insights into the involvement of this receptor in RCT. In this review, we discuss the molecular and cellular pathways involved in macrophage cholesterol efflux and cholesterol disposition, as well as recent clinical trials aimed at better understanding HDL function. Specifically, we address new advances in HDL biology that challenge longstanding misperceptions about HDL and cholesterol efflux from arterial wall and nonarterial wall sites through the use of specific terminology that addresses the various tissue locations involved in cholesterol efflux and elimination (Table 1). However, nonmacrophage arterial wall efflux and nonarterial wall cholesterol efflux are not addressed in this review. Critical to understanding the processes that facilitate arterial cholesterol efflux, recent experimental studies establish that increased fecal sterol excretion is not necessarily a prerequisite for HDL-mediated macrophage cholesterol efflux and atheroprotection. 10, 11 Thus, this new information necessitates revision of initial models of RCT to foster accurate description of the critical steps required for effective HDL-mediated atheroprotection.